Crosstalk between integrin and receptor tyrosine kinase...

BMB reports

311http://bmbreports.org BMB reports

*Corresponding author. Tel: 318-675-8797; Fax: 318-675-5180;E-mail: [email protected]

Received 1 May 2010

Keywords: Breast carcinoma progression, Crosstalk, Growth factor receptors, Integrin, Invasion, Survival

Crosstalk between integrin and receptor tyrosine kinase signaling in breast carcinoma progressionYoung Hwa Soung, John L. Clifford & Jun Chung*

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

This review explored the mechanism of breast carcinoma pro-gression by focusing on integrins and receptor tyrosine kinases (or growth factor receptors). While the primary role of integrins was previously thought to be solely as mediators of adhesive interactions between cells and extracellular matrices, it is now believed that integrins also regulate signaling pathways that control cancer cell growth, survival, and invasion. A large body of evidence suggests that the cooperation between in-tegrin and receptor tyrosine kinase signaling regulates certain signaling functions that are important for cancer progression. Recent developments on the crosstalk between integrins and receptor tyrosine kinases, and its implication in mammary tu-mor progression, are discussed. [BMB reports 2010; 43(5): 311-318]

INTRODUCTION

Cancer progression is a multi-step process that enables tumor cells to invade through extracellular tissues and metastasize to distal organs (1). Compelling recent evidence demonstrates that cooperation between signals from the extracellular matrix (ECM) and growth factors enhances malignant behaviors of ag-gressive cancer cells, such as proliferation, migration, survival, and invasion (2). Intracellular signals generated by growth fac-tors and their receptor tyrosine kinases (RTKs) are generated in-dependently from those produced by interaction between the ECM and integrin, and the synergy between these signals plays an important role in tumor growth and metastasis (3). There-fore, defining the mechanism by which these two signaling pathways cooperate is essential for understanding cancer pro-gression.

This review focuses on the evidence for crosstalk between integrin and RTKs in breast carcinoma progression. Breast can-cer is the most common form of cancer among women and is the second leading cause of cancer-related death (4). Breast

cancer originates from breast epithelial cells that are trans-formed into metastatic carcinomas. Metastatic potential and re-sponsiveness to treatment vary depending on the expression of hormone receptors such as estrogen receptor and progesterone receptor (5), RTKs such as ErbB-2, epidermal growth factor re-ceptor (EGFR), and hepatocyte growth factor receptor, c-Met (6), and integrins (7). Major integrins expressed on breast epi-thelial cells include α2β1, α3β1, αvβ3, αvβ5, αvβ6, α5β1, α6β1, and α6β4 (7). Among these, this review focuses on αvβ3, α5β1, and α6β4, all of which are upregulated in in-vasive breast carcinoma and have well established relation-ships with RTKs (8). These integrins serve as receptors for vi-tronectin, fibronectin, and laminin, respectively (9), and con-tribute to the survival and invasion of mammary tumors. Model systems describing the mechanisms and relevance of these integrin-RTK interactions will be discussed.

Integrin interaction with ECM

Integrins represent a major family of receptors that mediate cell adhesion to the ECM. To date, at least 18 α and 8 β in-tegrin subunits have been discovered (10). These non-homolo-gous, transmembrane α and β subunits dimerize to form 24 different integrins, each with distinct and sometimes over-lapping specificities for various ECM proteins. While the pri-mary role of integrins was thought to be as mediators of adhe-sive function, integrins also regulate cellular biological proc-esses related to cell morphology, proliferation, survival, migra-tion, and invasion (11). In other words, integrins relay cues from the ECM to intracellular signaling machinery upon ligand binding, a process called "Outside-in Signaling" (9). On the other hand, intracellular signaling activated by other receptors could induce conformational changes in integrins, thus alter-ing their functional activity, a process called "Inside-out Signa-ling" (12). Therefore, integrins and RTKs can exchange or am-plify their signaling pathways via both "Outside-in" and "Inside-out" signaling.

Downstream signaling events induced by integrin-ECM in-teractions include Ras, Phosphop-inositol-3-kinase (PI3 Kinase), MAP kinase, focal adhesion kinase (FAK), Src, Akt, integrin- linked kinase (ILK), Abl and Rac, Rho, and cdc42 small GTPases (13-16). In addition, integrin-ECM interactions induce the phosphorylation of key tyrosine residues of integrin sub-

Mini Review

Crosstalk between integrins and RTKsYoung Hwa Soung, et al.

312 BMB reports http://bmbreports.org

Fig. 1. Signaling pathways mediated by α6β4 integrin-RTKs crosstalk. α6β4 integrin in Hemidesmosomes (HDs) has no signaling function but does provide structural support to the epithelia. The tumor microenvironment induces PKC-α-dependent phosphorylation of key Ser res-idues in the β4 integrin cytoplasmic tail, resulting in HD disassembly. Mobilization of α6β4 from HDs allows association of α6β4 with actin filament-rich sub domains of membrane structures in which functional interactions with RTKs occur, such as lipid rafts. Several exam-ples in which α6β4 associates with RTKs are shown. (A) α6β4 is physically and functionally associated with ErbB2 and EGFR. The associ-ation of EGFR with α6β4 is mediated by SFKs (Fyn) activation. (B) MSP induces association of α6β4 with Ron through 14-3-3, which acts as a linker molecule. (C) Cooperative signaling between α6β4 and c-Met is responsible for various aspects of breast cancer progression, al-though the constitutive and physical interaction between c-Met and α6β4 remains controversial. PI-3K/Ras are major downstream signaling pathways mediated by α6β4-RTK crosstalk.

units such as β3 and β4, which results in recruitment of signal-ing adaptor molecules such as Shc, Shp-2, and Crk (17-19). These adaptor molecules not only transmit integrin-dependent signals, but also contribute to crosstalk with other signaling re-ceptors including RTKs (20-22). It is interesting to note that in-tracellular signaling events activated by integrin ligation are al-so influenced by growth factor stimulation. Indeed, integrin- ECM interactions significantly amplify growth factor-mediated signaling events (23), which suggests that synergy between in-tegrin and RTK signaling could maximize biochemical res-ponses.

Evidence for integrin and RTK crosstalk

Considering that neither α nor β integrin subunits possess cata-lytic activity, it is possible that multiple mechanisms may regu-late crosstalk between integrins and RTKs. The most compel-ling evidence comes from direct, physical association between integrins and RTKs. Co-immunoprecipitation assays have been used to identify biochemical interactions between these recep-

tors. For example, αvβ3 integrin associates with insulin-like growth factor receptor (IGFR-1), platelet-derived growth factor receptor (PDGFR) (24, 25), and vascular endothelial growth factor receptor-2 (VEGFR2) (26). Additionally, α6β4 integrin has been shown to associate with ErbB2 (27), c-Met (28), EGFR (20), and Ron (29). These associations suggest that signaling cooperation between integrins and RTKs may be the result of receptor co-clustering upon cell adhesion or growth factor stimulation. Growth factor stimulation of RTKs or ECM-integrin interactions induces an increase in the local concentration of integrins and RTKs at focal adhesions and at leading edges of carcinoma cells, such that crosstalk could occur even without direction physical association by alteration of the intracellular localization of integrins (30).

The mode of signaling cooperation between integrins and RTKs could be reciprocal as well as uni-directional. Bi-direc-tional cooperation between the two signaling systems was demonstrated for the αvβ3-IGF receptor (31) and αvβ3-PDGF-α complex (32), whereupon signaling pathways activated by both integrin engagement and growth factors converge down-



stream at common signaling effectors. Uni-directional, in-tegrin-dependent RTK activation was demonstrated for β1 in-tegrin-dependent EGFR activation (21). β1 integrin ligation by adhesion leads to the c-Src dependent recruitment of EGFR and p130Cas, and subsequently to phosphorylation and activa-tion of EGFR in an EGF-independent manner (21). Finally, α6β4 integrin is an example of uni-directional, growth fac-tor-dependent integrin activation. Growth factor-dependent ac-tivation of EGFR and c-Met increases the phosphorylation of key serine and tyrosine residues of the β4 integrin cytoplasmic tail (20, 33-35). Phosphorylated α6β4 amplifies EGFR and c-Met signaling in a ligand-independent manner, since an ex-tracellular domain deletion mutant of β4 integrin could still mediate crosstalk (36).

α6β4 integrin and RTK association

α6β4 integrin is a receptor of the laminin family of extra-cellular matrix proteins, although increasing evidence suggests that it can signal independently of laminin binding (30, 37, 38). Due to its ubiquitous expression in most epithelial cells, α6β4 was originally thought to maintain the integrity of epi-thelia based on its ability to mediate the formation of hemi-desmosomes (HDs), which are responsible for linking inter-mediate filaments with laminins in the basement membrane (38, 39). However, recent evidence has established that this integrin is associated with reduced survival and poor prognosis in a number of human cancers (39-41). Our studies and others also confirmed that α6β4 has functions associated with carci-noma progression (28, 42, 43). The remaining question, there-fore, is how α6β4 integrin could exert two different functions in normal epithelia vs. aggressive carcinoma cells. The current model states that α6β4 in epithelial cells simply contributes to tissue integrity and structural support via association with HDs, whereas in carcinoma cells the tumor microenvironment leads to EGFR/PKC-α- dependent phosphorylation of the β4 in-tegrin cytoplasmic tail at specific Ser residues, which then in-duces disassembly of HDs (Fig. 1) (33, 34). Subsequent mobi-lization of α6β4 from HDs is essential for signaling and is characteristic of invasive carcinoma cells (30). Once released from HDs, Cys residues of the membrane proximal region of β4 integrin are palmitoylated, which allows α6β4 to be in-corporated into lipid rafts (33, 34). Lipid rafts are sphingolipid, cholesterol-rich microdomains of the plasma membrane that contain many signaling receptors all of which are in close proximity (44, 45). Once α6β4 localizes to lipid rafts, its sig-naling function is supposedly enhanced through crosstalk with signaling receptors such as RTKs, since lipid rafts are rich in RTKs. The signaling competent form of α6β4 has the potential to form complexes with specific RTKs that mediate key signal-ing pathways essential to breast carcinoma behavior (Fig. 1).

The first evidence for the association of α6β4 with RTKs came from studies involving EGFR family members. Falcioni et al demonstrated that α6β4 integrin may associate with ErbB2,

an orphan receptor of the EGFR family, in several breast carci-noma cells (27, 46). This association is required for the PI3K/ AKT pathway to stimulate α6β4-dependent breast carcinoma cell motility and invasion (47). α6β4 also enhances ErbB3 ex-pression in breast cancer cells, and cooperation between these two receptors is required for PI3K activation (48). EGFR con-tributes to α6β4-dependent invasion via disruption of hemi-desmosomes (HD) as well as subsequent activation of Fyn, a Src family kinase (20, 33). A more recent report demonstrated that crosslinking of α6β4 results in the clustering of EGFR on the plasma membrane of breast carcinoma cells, which pro-motes Rho activation for the enhancement of cell motility and invasion (49).

Another example of the α6β4-RTK interaction was demon-strated by its relationship with the Hepatocyte growth factor (HGF) receptor, c-Met. Trusolino et al demonstrated that α6β4 physically associates with c-Met, functioning as an adaptor molecule for the amplification of c-Met signaling in invasive breast carcinoma cells (28). Additional studies showed that HGF stimulation mediates tyrosine phosphorylation of the β4 integrin subunit and enhances anchorage-independent growth of breast cancer cells through Gab1 and Src (17). While the constitutive and physical interaction between α6β4 and c-Met remains controversial (50), it appears that their functional inter-actions play a key role in breast carcinoma progression. The first study to explain the mechanism of α6β4-RTK complex for-mation was conducted by Santoro et al. (29). Macrophage stimulating protein (MSP) receptor, Ron (a c-Met related kin-ase), stimulates PKC-dependent auto-phosphorylation as well as phosphorylation of β4 integrin upon MSP activation in kera-tinocytes. Phosphorylated Ron and α6β4 are able to recruit 14-3-3, which acts as a linker molecule in the formation of a Ron-α6β4 complex (29). These data suggest that formation of the integrin-RTK complex can be triggered by oncogenic sti-muli. Altogether, it is apparent that the α6β4-RTK interaction contributes to various aspects of carcinoma behavior, although the precise nature of their interaction remains to be deter-mined.

αvβ3 integrin and RTK association

The αvβ3 integrin is a vitronectin binding receptor whose ex-pression is upregulated in metastatic breast carcinoma cells (51, 52). Due to its high expression in both breast tumor and angiogenic epithelial cells, αvβ3 is an attractive therapeutic tar-get. The αvβ3 blocking antibodies LM609 and etaracizumab, a humanized version of LM609, are currently being tested in clinical trials and have been shown to effectively block both angiogenic activity (53) and bone metastsis (54).

Multiple RTKs has been shown to associate with αvβ3 (55), and the blocking ligand occupancy of αvβ3 reduces RTK sig-naling (Fig. 2). For example, αvβ3-mediated adhesion enhan-ces IGFR-1 signaling, since inhibition of αvβ3 ligand occu-pancy by the disintegrin echistatin reduces phosphorylation of



Fig. 2. Signaling pathways mediated by αvβ3 integrin-RTKs crosstalk. (A) IGFR-1 requires vitronectin binding of αvβ3 for maximal IGF-1 response, such as MAPK activation and carcinoma cell motility. Blockage of ligand binding to αvβ3 recruits the tyrosine phosphatase Shp2 and reduces IGFR1 phosphorylation. (B) Crosstalk between αvβ3 and c-Met is involved in OPN-induced carcinoma migration, leading to bone metastasis of breast carcinoma. (C) VEGF stimulates c-Src-dependent phosporylation of the β3 cytoplasmic domain, leading to com-plex formation between αvβ3 and VEGFR. αvβ3 and c-Met complex are involved in PI-3K activation and the angiogenic response. (D) PDGF stimulation induces Shc-dependent αvβ3-PDGF complex formation that contributes to carcinoma proliferation.

IGFR-1 by recruiting the tyrosine phosphatase Shp2 (Malie 2002). αvβ3 also cooperates with c-Met to enhance OPN (osteopontin)- induced mammary epithelial cell migration (56, 57). This evi-dence suggests a potential role for the αvβ3-RTK complex in bone metastasis of breast cancer. Association between PDGFR and αvβ3 was demonstrated in oligodendrocytes (32, 58), and PDGF-dependent mitogenic activity requires association be-tween αvβ3 and PDGFR. PKC mediates PDGF-induced activa-tion of αvβ3, which leads to an increase in matrix binding of αvβ3 and αvβ3-dependent oligodendrocyte proliferation.

In addition to its role in vitronectin-dependent migration and proliferation, αvβ3 contributes to angiogenesis through physical and functional interactions with vascular endothelial growth factor receptor-2 (VEGFR2) (26, 59). Treatment with a ligand blocking antibody against αvβ3 integrin inhibits VEGF- stimulated VEGFR-2 phosphorylation (26). VEGF stimulation leads to c-Src dependent phosphorylation of the β3 cytoplas-mic domain (Y747, Y759), which contributes to physical asso-ciation of αvβ3 with VEGFR2 (22, 60). Finally, a novel para-digm for integrin-RTK crosstalk was recently reported that showed Fibroblast growth factor-1 (FGF1) directly binds to αvβ3, which regulates FGF1-dependent angiogenesis via ex-tracellular signal-regulated kinase (Erk) and Akt (61). All these data suggest that the αvβ3-RTK complex has multiple roles in carcinoma progression, including migration, invasion, bone metastasis, and angiogenesis (Fig. 2). Therefore, targeting path-

ways that induce αvβ3-RTK interaction are attractive strategies for developing novel anti-cancer therapeutics.

α5β1 integrin and RTK association

α5β1 Integrin is the major receptor for fibronectin (62) and contributes to breast cancer survival and metastasis. Both ele-vated levels and activity of α5β1 have been implicated in drug-resistant breast carcinoma cells (63). The mechanism by which α5β1 promotes invasion of breast carcinoma cells in-volves the recruitment or activation of matrix metalloproteinase 2 (MMP-2) collagenase on the cell surface (64). The α5β1- fibronectin interaction also causes constitutive invasiveness of prostate cancer cells via MMP-1 activation, indicating its major role in matrix metalloproteinase regulation (65). Further, α5β1- RTK interactions were reported to contribute to the invasive phenotype of cancer cells (Fig. 3). While the major ligand of α5β1 is fibronectin, fibrinogen and urokinase type plasmi-nogen activator receptor (uPAR) can also interact with α5β1 as ligands. For example, activated EGFR and uPAR form a ternary complex with α5β1 that promotes cancer cell migration, in-vasion, proliferation, and survival by activation of the ERK pathway (66). The results suggest that, in aggressive carcinoma cells, α5β1 can interact with EGFR through overexpression of uPAR.

In addition to its role in carcinoma cell invasion, α5β1 is



Fig. 3. Signaling mediated by α5β1 integrin-RTKs crosstalk. (A) uPAR and fibronectin form a ternary complex that contains uPAR, EGFR, and α5β1 resulting in activation of the Erk pathway. (B) Ang-1 stimulation induces α5β1-Tie2 association, which recruits the p85 subunit of PI-3K along with FAK to the α5 cytoplasmic domain. This interaction is implicated in PI3K-mediated angiogenesis. (C) α5β1 forms a complex with EGFR via recruitment of p85 to α5β1 through ErbB3 phosphorylation, resulting in PI3K activation. (D) HGF forms het-ero-complexes with the matrix ligands (vitronectin and fivronectin) of αvβ3 and α5β1 These hetero-complexes promote interaction of c-Met with αvβ3 and α5β1.

implicated in the regulation of endothelial cell function and angiogenesis through the Tie-2 receptor, which binds to An-giopoetin-1 (Ang-1) and Angiopoetin-2 (Ang-2) (67). In endo-thelial cells, the physical interaction of α5β1 and Tie2 with Ang1 results in the phosphorlyation of the p85 subunit of PI3K as well as FAK and the efficient transmission of PI3K/AKT sig-nals (67). Consistent with this evidence, a study demonstrated that functional association of α5β1 with VEGFR3 plays a role in the proliferation of lymphatic endothelial cells and angio-genesis through activation of the PI3k/AKT pathway (68). In another example, α5β1 complexes with EGFR and ErbB3 in in-testinal epithelial cells, which leads to recruitment of p85 to the EGFR-α5β1 complex through ErbB3 phosphorylation fol-lowed by enhanced PI3K signaling. However, the nature of this ternary complex remains to be determined (69).

Finally, the HGF receptor c-Met, which associates with α6β4 and αvβ3, also interacts with α5β1 (70). It is interesting to note that the c-Met ligand HGF forms hetero-complexes with vitronectin and fibronectin, allowing simultaneous associ-ation of c-Met with αvβ3 and α5β1 (70). Indeed, the activity and phosphorylation level of c-Met in the presence of vi-tronectin and fibronectin were significantly enhanced by for-mation of this heterocomplex (71). Overall, these studies dem-onstrate the importance of the α5β1-RTK complex in regulat-ing carcinoma invasion as well as in vascular stabilization that is essential for angiogenesis (Fig. 3).

Summary

Collaborative activity between integrins and RTKs provide a mechanism for signaling systems important to carcinoma progression. This review summarized multiple examples in which breast carcinoma cells respond to environmental cues related to growth factors and extracellular matrix molecules by focusing on integin-RTK interactions. Further study will con-tinue to generate insights into the molecular mechanisms un-derlying the physical and functional partnerships between these receptors. Eventually, such data will provide the basis for developing novel therapeutic interventions that target the inter-action between integrins and RTKs.

Acknowledgements US Army Medical Research Program Grant (BC001077) and Wendy Will Case Cancer Foundation Grant supported the work discussed in this review from the author’s laboratory.

REFERENCES

1. Hanahan, D. and Weinberg, R. A. (2000) The hallmarks of cancer. Cell 100, 57-70.

2. Larsen, M., Artym, V. V., Green, J. A. and Yamada, K. M. (2006) The matrix reorganized: extracellular matrix re-modeling and integrin signaling. Curr. Opin. Cell Biol. 18,



463-471.3. Giancotti, F. G. and Ruoslahti, E. (1999) Integrin sig-

naling. Science 285, 1028-1032.4. Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M.,

Jeffrey, S. S., Rees, C. A., Pollack, J. R., Ross, D. T., Johnsen, H., Akslen, L. A., Fluge, O., Pergamenschikov, A., Williams, C., Zhu, S. X., Lonning, P. E., Borresen-Dale, A. L., Brown, P. O. and Botstein, D. (2000) Molecular portraits of human breast tumours. Nature 406, 747-752.

5. Nielsen, T. O., Hsu, F. D., Jensen, K., Cheang, M., Karaca, G., Hu, Z., Hernandez-Boussard, T., Livasy, C., Cowan, D., Dressler, L., Akslen, L. A., Ragaz, J., Gown, A. M., Gilks, C. B., van de Rijn, M. and Perou, C. M. (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin. Cancer Res. 10, 5367-5374.

6. Byers, S., Park, M., Sommers, C. and Seslar, S. (1994) Breast carcinoma: a collective disorder. Breast Cancer Res. Treat. 31, 203-215.

7. Shaw, L. M. (1999) Integrin function in breast carcinoma progression. J. Mammary. Gland. Biol. Neoplasia. 4, 367-376.

8. Aumailley, M., Pesch, M., Tunggal, L., Gaill, F. and Fassler, R. (2000) Altered synthesis of laminin 1 and ab-sence of basement membrane component deposition in (beta)1 integrin-deficient embryoid bodies. J. Cell Sci. 113 Pt 2, 259-268.

9. Plow, E. F., Haas, T. A., Zhang, L., Loftus, J. and Smith, J. W. (2000) Ligand binding to integrins. J. Biol. Chem. 275, 21785-21788.

10. van der Flier, A. and Sonnenberg, A. (2001) Function and interactions of integrins. Cell Tissue. Res. 305, 285-298.

11. Aplin, A. E., Howe, A. K. and Juliano, R. L. (1999) Cell ad-hesion molecules, signal transduction and cell growth. Curr. Opin. Cell Biol. 11, 737-744.

12. Luo, B. H., Carman, C. V. and Springer, T. A. (2007) Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619-647.

13. Bryan, B. A. and D'Amore, P. A. (2007) What tangled webs they weave: Rho-GTPase control of angiogenesis. Cell Mol. Life Sci. 64, 2053-2065.

14. Kanda, S., Kanetake, H. and Miyata, Y. (2007) Role of Src in angiopoietin 1-induced capillary morphogenesis of en-dothelial cells: effect of chronic hypoxia on Src inhibition by PP2. Cell Signal 19, 472-480.

15. Ridley, A. (2000) Rho GTPases. Integrating integrin signaling. J. Cell Biol. 150, F107-109.

16. Schwartz, M. A. and Shattil, S. J. (2000) Signaling net-works linking integrins and rho family GTPases. Trends Biochem. Sci. 25, 388-391.

17. Bertotti, A., Comoglio, P. M. and Trusolino, L. (2006) Beta4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth. J. Cell Biol. 175, 993-1003.

18. Klemke, R. L., Leng, J., Molander, R., Brooks, P. C., Vuori, K. and Cheresh, D. A. (1998) CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. J. Cell Biol. 140, 961-972.

19. Collins, L. R., Ricketts, W. A., Yeh, L. and Cheresh, D. (1999) Bifurcation of cell migratory and proliferative sig-

naling by the adaptor protein Shc. J. Cell Biol. 147, 1561- 1568.

20. Mariotti, A., Kedeshian, P. A., Dans, M., Curatola, A. M., Gagnoux-Palacios, L. and Giancotti, F. G. (2001) EGF-R signaling through Fyn kinase disrupts the function of in-tegrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J. Cell Biol. 155, 447-458.

21. Moro, L., Dolce, L., Cabodi, S., Bergatto, E., Boeri Erba, E., Smeriglio, M., Turco, E., Retta, S. F., Giuffrida, M. G., Venturino, M., Godovac-Zimmermann, J., Conti, A., Schae-fer, E., Beguinot, L., Tacchetti, C., Gaggini, P., Silengo, L., Tarone, G. and Defilippi, P. (2002) Integrin-induced epi-dermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specif-ic EGF receptor tyrosines. J. Biol. Chem. 277, 9405-9414.

22. Mahabeleshwar, G. H., Feng, W., Reddy, K., Plow, E. F. and Byzova, T. V. (2007) Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis. Circ. Res. 101, 570-580.

23. Somanath, P. R., Kandel, E. S., Hay, N. and Byzova, T. V. (2007) Akt1 signaling regulates integrin activation, matrix recognition, and fibronectin assembly. J. Biol. Chem. 282, 22964-22976.

24. Schneller, M., Vuori, K. and Ruoslahti, E. (1997) Alphav-beta3 integrin associates with activated insulin and PDGF beta receptors and potentiates the biological activity of PDGF. EMBO J. 16, 5600-5607.

25. Borges, E., Jan, Y. and Ruoslahti, E. (2000) Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. J. Biol. Chem. 275, 39867-39873.

26. Soldi, R., Mitola, S., Strasly, M., Defilippi, P., Tarone, G. and Bussolino, F. (1999) Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor re-ceptor-2. EMBO J. 18, 882-892.

27. Falcioni, R., Antonini, A., Nistico, P., Di Stefano, S., Crescenzi, M., Natali, P. G. and Sacchi, A. (1997) Alpha 6 beta 4 and alpha 6 beta 1 integrins associate with ErbB-2 in human carcinoma cell lines. Exp. Cell Res. 236, 76-85.

28. Trusolino, L., Bertotti, A. and Comoglio, P. M. (2001) A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell 107, 643-654.

29. Santoro, M. M., Gaudino, G. and Marchisio, P. C. (2003) The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration. Dev. Cell 5, 257-271.

30. Lipscomb, E. A. and Mercurio, A. M. (2005) Mobilization and activation of a signaling competent alpha6beta4in-tegrin underlies its contribution to carcinoma progression. Cancer Metastasis Rev. 24, 413-423.

31. Maile, L. A. and Clemmons, D. R. (2002) The alphaVbeta3 integrin regulates insulin-like growth factor I (IGF-I) re-ceptor phosphorylation by altering the rate of recruitment of the Src-homology 2-containing phosphotyrosine phos-phatase-2 to the activated IGF-I receptor. Endocrinology 143, 4259-4264.

32. Baron, W., Shattil, S. J. and ffrench-Constant, C. (2002)



The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of alpha(v)beta3 integrins. EMBO J. 21, 1957-1966.

33. Rabinovitz, I., Toker, A. and Mercurio, A. M. (1999) Protein kinase C-dependent mobilization of the alpha 6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic mi-gration of carcinoma cells. J. Cell Biol. 146, 1147-1160.

34. Rabinovitz, I., Tsomo, L. and Mercurio, A. M. (2004) Pro-tein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes. Mol. Cell Biol. 24, 4351-4360.

35. Germain, E. C., Santos, T. M. and Rabinovitz, I. (2009) Phosphorylation of a novel site on the {beta}4 integrin at the trailing edge of migrating cells promotes hemi-desmosome disassembly. Mol. Biol. Cell 20, 56-67.

36. Trusolino, L. and Comoglio, P. M. (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat. Rev. Cancer 2, 289-300.

37. Mercurio, A. M., Bachelder, R. E., Rabinovitz, I., O'Connor, K. L., Tani, T. and Shaw, L. M. (2001) The metastatic odyssey: the integrin connection. Surg. Oncol. Clin. N. Am. 10, 313-328.

38. Nguyen, B. P., Ryan, M. C., Gil, S. G. and Carter, W. G. (2000) Deposition of laminin 5 in epidermal wounds reg-ulates integrin signaling and adhesion. Curr. Opin. Cell Biol. 12, 554-562.

39. Mercurio, A. M., Bachelder, R. E., Bates, R. C. and Chung, J. (2004) Autocrine signaling in carcinoma: VEGF and the alpha6beta4 integrin. Semin. Cancer Biol. 14, 115-122.

40. Chung, J. and Mercurio, A. M. (2004) Contributions of the alpha6 integrins to breast carcinoma survival and pro-gression. Mol. Cells 17, 203-209.

41. Mercurio, A. M. and Rabinovitz, I. (2001) Towards a me-chanistic understanding of tumor invasion--lessons from the alpha6beta 4 integrin. Semin. Cancer Biol. 11, 129- 141.

42. Chung, J., Bachelder, R. E., Lipscomb, E. A., Shaw, L. M. and Mercurio, A. M. (2002) Integrin (alpha 6 beta 4) regu-lation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. J. Cell Biol. 158, 165- 174.

43. Mercurio, A. M., Rabinovitz, I. and Shaw, L. M. (2001) The alpha 6 beta 4 integrin and epithelial cell migration. Curr. Opin. Cell Biol. 13, 541-545.

44. Head, B. P., Patel, H. H., Roth, D. M., Murray, F., Swaney, J. S., Niesman, I. R., Farquhar, M. G. and Insel, P. A. (2006) Microtubules and actin microfilaments regu-late lipid raft/caveolae localization of adenylyl cyclase sig-naling components. J. Biol. Chem. 281, 26391-26399.

45. de Laurentiis, A., Donovan, L. and Arcaro, A. (2007) Lipid rafts and caveolae in signaling by growth factor receptors. Open Biochem. J. 1, 12-32.

46. Guo, W., Pylayeva, Y., Pepe, A., Yoshioka, T., Muller, W. J., Inghirami, G. and Giancotti, F. G. (2006) Beta 4 in-tegrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126, 489-502.

47. Gambaletta, D., Marchetti, A., Benedetti, L., Mercurio, A. M., Sacchi, A. and Falcioni, R. (2000) Cooperative signal-

ing between alpha(6)beta(4) integrin and ErbB-2 receptor is required to promote phosphatidylinositol 3-kinase- dependent invasion. J. Biol. Chem. 275, 10604-10610.

48. Folgiero, V., Bachelder, R. E., Bon, G., Sacchi, A., Falcioni, R. and Mercurio, A. M. (2007) The alpha6beta4 integrin can regulate ErbB-3 expression: implications for alpha6 beta4 signaling and function. Cancer Res. 67, 1645-1652.

49. Gilcrease, M. Z., Zhou, X., Lu, X., Woodward, W. A., Hall, B. E. and Morrissey, P. J. (2009) Alpha6beta4 in-tegrin crosslinking induces EGFR clustering and promotes EGF-mediated Rho activation in breast cancer. J. Exp. Clin. Cancer Res. 28, 67.

50. Chung, J., Yoon, S. O., Lipscomb, E. A. and Mercurio, A. M. (2004) The Met receptor and alpha 6 beta 4 integrin can function independently to promote carcinoma invasion. J. Biol. Chem. 279, 32287-32293.

51. Meyer, T., Marshall, J. F. and Hart, I. R. (1998) Expression of alphav integrins and vitronectin receptor identity in breast cancer cells. Br. J. Cancer 77, 530-536.

52. Wong, N. C., Mueller, B. M., Barbas, C. F., Ruminski, P., Quaranta, V., Lin, E. C. and Smith, J. W. (1998) Alphav in-tegrins mediate adhesion and migration of breast carcino-ma cell lines. Clin. Exp. Metastasis. 16, 50-61.

53. Brooks, P. C., Stromblad, S., Klemke, R., Visscher, D., Sarkar, F. H. and Cheresh, D. A. (1995) Antiintegrin alpha v beta 3 blocks human breast cancer growth and angio-genesis in human skin. J. Clin. Invest. 96, 1815-1822.

54. Gramoun, A., Shorey, S., Bashutski, J. D., Dixon, S. J., Sims, S. M., Heersche, J. N. and Manolson, M. F. (2007) Effects of Vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro. J. Cell Biochem. 102, 341-352.

55. Eliceiri, B. P. (2001) Integrin and growth factor receptor crosstalk. Circ. Res. 89, 1104-1110.

56. Tuck, A. B., Elliott, B. E., Hota, C., Tremblay, E. and Chambers, A. F. (2000) Osteopontin-induced, integrin- dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor re-ceptor (Met). J. Cell Biochem. 78, 465-475.

57. White, D. E. and Muller, W. J. (2007) Multifaceted roles of integrins in breast cancer metastasis. J. Mammary. Gland. Biol. Neoplasia. 12, 135-142.

58. Colognato, H., Baron, W., Avellana-Adalid, V., Relvas, J. B., Baron-Van Evercooren, A., Georges-Labouesse, E. and ffrench-Constant, C. (2002) CNS integrins switch growth factor signalling to promote target-dependent survival. Nat. Cell Biol. 4, 833-841.

59. Somanath, P. R., Malinin, N. L. and Byzova, T. V. (2009) Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis. Angiogenesis 12, 177-185.

60. Phillips, D. R., Prasad, K. S., Manganello, J., Bao, M. and Nannizzi-Alaimo, L. (2001) Integrin tyrosine phosphor-ylation in platelet signaling. Curr. Opin. Cell Biol. 13, 546-554.

61. Mori, S., Wu, C. Y., Yamaji, S., Saegusa, J., Shi, B., Ma, Z., Kuwabara, Y., Lam, K. S., Isseroff, R. R., Takada, Y. K. and Takada, Y. (2008) Direct binding of integrin alphavbe-ta3 to FGF1 plays a role in FGF1 signaling. J. Biol. Chem. 283, 18066-18075.

62. Danen, E. H. and Yamada, K. M. (2001) Fibronectin, in-



tegrins, and growth control. J. Cell Physiol. 189, 1-13.63. Nista, A., Leonetti, C., Bernardini, G., Mattioni, M. and

Santoni, A. (1997) Functional role of alpha4beta1 and al-pha5beta1 integrin fibronectin receptors expressed on adriamycin-resistant MCF-7 human mammary carcinoma cells. Int. J. Cancer 72, 133-141.

64. Morozevich, G., Kozlova, N., Cheglakov, I., Ushakova, N. and Berman, A. (2009) Integrin alpha5beta1 controls in-vasion of human breast carcinoma cells by direct and in-direct modulation of MMP-2 collagenase activity. Cell Cycle 8, 2219-2225.

65. Jia, Y., Zeng, Z. Z., Markwart, S. M., Rockwood, K. F., Ignatoski, K. M., Ethier, S. P. and Livant, D. L. (2004) Integrin fibronectin receptors in matrix metalloproteinase- 1-dependent invasion by breast cancer and mammary epi-thelial cells. Cancer Res. 64, 8674-8681.

66. Liu, Y., Pixley, R., Fusaro, M., Godoy, G., Kim, E., Bromberg, M. E. and Colman, R. W. (2009) Cleaved high-molecular-weight kininogen and its domain 5 inhibit migration and invasion of human prostate cancer cells through the epidermal growth factor receptor pathway. Oncogene 28, 2756-2765.

67. Cascone, I., Napione, L., Maniero, F., Serini, G. and Bu-

ssolino, F. (2005) Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endo-thelial cell response to Ang-1. J. Cell Biol. 170, 993-1004.

68. Zhang, X., Groopman, J. E. and Wang, J. F. (2005) Ex-tracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5beta1. J. Cell Physiol. 202, 205-214.

69. Lee, J. W. and Juliano, R. L. (2002) The alpha5beta1 in-tegrin selectively enhances epidermal growth factor sig-naling to the phosphatidylinositol-3-kinase/Akt pathway in intestinal epithelial cells. Biochim. Biophys. Acta. 1542, 23-31.

70. Rahman, S., Patel, Y., Murray, J., Patel, K. V., Sumathipa-la, R., Sobel, M. and Wijelath, E. S. (2005) Novel hep-atocyte growth factor (HGF) binding domains on fi-bronectin and vitronectin coordinate a distinct and ampli-fied Met-integrin induced signalling pathway in endothe-lial cells. BMC. Cell Biol. 6, 8.

71. Bell, L. N., Cai, L., Johnstone, B. H., Traktuev, D. O., March, K. L. and Considine, R. V. (2008) A central role for hepatocyte growth factor in adipose tissue angiogenesis. Am. J. Physiol. Endocrinol. Metab. 294, E336-344.

Crosstalk between integrin and receptor tyrosine kinase...

Documents

Transcript of Crosstalk between integrin and receptor tyrosine kinase...