The integrin alpha6beta4 was discovered in the late 1980s by two different groups and was called either alphaEbeta4 or Ic-Ic binding protein (Ic-IcBP) (1,2). The alpha6beta4 integrin is a component of Hemidesmosomes (HDs) (3, 4,5). Increased expression of alphaEbeta4 and changes in its distribution is found to be correlated with increased aggressiveness of tumors and poor prognosis (6, 7). Although integrin alpha6beta4, can interact with different laminin isoforms, its preferred ligand in the epidermal BM is laminin-5 (8, 9). The beta4 integrin is a large protein and has a cytoplasmic domain of more than 1000 amino acids (10, 11). This domain contains a Na-Ca exchanger (CalX) motif followed by two pairs of type III fibronectin (FNIII) domains separated by a connecting segment (CS). It is found to associate with the intermediate filament system through plectin and BP230, which are components of hemidesmosomes (12,13,14). Interaction of intgrin beta4 with components of hemidesmosomes including plectin, BP230 and BP180 is found to be important in signaling events associated with cell growth, survival, and migration under physiological and pathological conditions.
Studies have shown that beta4 can regulate keratinocyte migration both positively and negatively (15,16,17,18). It is also found to regulate cell survival in keratinocytes in cell culture systems under stress in a PI3K/Akt pathway dependent manner (19,18). However, alpha6beta4 was not found to have any effect on keratinocyte survival in vivo (20, 18, 16). Apart from its effects on keratinocytes, evidence suggests that integrin alpha6beta4 is important in cancer cell invasion (21,22,23,24) and survival (25,26,27,28,16,29). The cancer cell invasion is regulated through a IRS/PI3K dependent process while the effect on carcinoma cell survival in a PI3K/Akt and dependent manner. Activation of the transcription factors NFkappaB and NF-IL6 in a p38Mapk dependent pathway and subsequent activation of IL6 gene expression was shown to be mechanism of alpha6beta4 induced survival of thymocytes and proliferation of thymic epithelial cells (27,30). Integrin alpha6beta4 is also known activate the Ras/Raf/MEK/ERK cascade which is found to be involved in the regulation of cell cycle (31,32,33,34).
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5. Stepp MA, Spurr-Michaud S, Tisdale A, Elwell J, Gipson IK.Alpha 6 beta 4 integrin heterodimer is a component of hemidesmosomes.Proc Natl Acad Sci U S A.22,8970-4.
6. Falcioni R, Kennel SJ, Giacomini P, Zupi G, Sacchi A.Expression of tumor antigen correlated with metastatic potential of Lewis lung carcinoma and B16 melanoma clones in mice.Cancer Res. 11,5772-8
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8. Niessen CM, Hogervorst F, Jaspars LH, de Melker AA, Delwel GO, Hulsman EH, Kuikman I, Sonnenberg A.The alpha 6 beta 4 integrin is a receptor for both laminin and kalinin.Exp Cell Res. 2,360-7.
9. Rousselle P, Lunstrum GP, Keene DR, Burgeson RE.Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments.J Cell Biol. 3,567-76.
10. Hogervorst F, Kuikman I, von dem Borne AE, Sonnenberg A.Cloning and sequence analysis of beta-4 cDNA: an integrin subunit that contains a unique 118 kd cytoplasmic domain.EMBO J. 3,765-70.
11. Suzuki S, Naitoh Y.Amino acid sequence of a novel integrin beta 4 subunit and primary expression of the mRNA in epithelial cells.EMBO J.3,757-63.
12. Guo L, Degenstein L, Dowling J, Yu QC, Wollmann R, Perman B, Fuchs E.Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration.Cell.2,233-43.
13. Niessen CM, Hulsman EH, Rots ES, Sánchez-Aparicio P, Sonnenberg A.Integrin alpha 6 beta 4 forms a complex with the cytoskeletal protein HD1 and induces its redistribution in transfected COS-7 cells.Mol Biol Cell.4,555-66.
14. Rezniczek GA, de Pereda JM, Reipert S, Wiche G.Linking integrin alpha6beta4-based cell adhesion to the intermediate filament cytoskeleton: direct interaction between the beta4 subunit and plectin at multiple molecular sites.J Cell Biol. 1,209-25.
15. Geuijen CA, Sonnenberg A.Dynamics of the alpha6beta4 integrin in keratinocytes.Mol Biol Cell. 11,3845-58.
16. Raymond K, Kreft M, Janssen H, Calafat J, Sonnenberg A.Keratinocytes display normal proliferation, survival and differentiation in conditional beta4-integrin knockout mice.J Cell Sci. Pt 5,1045-60.
17. Russell AJ, Fincher EF, Millman L, Smith R, Vela V, Waterman EA, Dey CN, Guide S, Weaver VM, Marinkovich MP.Alpha 6 beta 4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of alpha 3 beta 1 integrin.J Cell Sci. Pt 17,3543-56.
18. Nikolopoulos SN, Blaikie P, Yoshioka T, Guo W, Puri C, Tacchetti C, Giancotti FG.Targeted deletion of the integrin beta4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-kappaB, causing defects in epidermal growth and migration.
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20. Raymond K, Kreft M, Janssen H, Calafat J, Sonnenberg A.Keratinocytes display normal proliferation, survival and differentiation in conditional beta4-integrin knockout mice.J Cell Sci.Pt 5,1045-60.
21. Shaw LM.Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion.Mol Cell Biol. 15,5082-93.
22. Shaw LM, Rabinovitz I, Wang HH, Toker A, Mercurio AM.Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion.Cell. 7,949-60.
23. Trusolino L, Bertotti A, Comoglio PM.A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth.Cell. 5,643-54.
24. Wang H, Fu W, Im JH, Zhou Z, Santoro SA, Iyer V, DiPersio CM, Yu QC, Quaranta V, Al-Mehdi A, Muschel RJ.Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis.J Cell Biol. 6,935-41.
25. Bachelder RE, Ribick MJ, Marchetti A, Falcioni R, Soddu S, Davis KR, Mercurio AM.p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB.
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26. Clarke AS, Lotz MM, Chao C, Mercurio AM.Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain.J Biol Chem. 39,22673-6.
27. Mainiero F, Colombara M, Antonini V, Strippoli R, Merola M, Poffe O, Tridente G, Ramarli D.p38 MAPK is a critical regulator of the constitutive and the beta4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells.Eur J Immunol. 11,3038-48.
28. Ramarli D, Scupoli MT, Fiorini E, Poffe O, Brentegani M, Villa A, Cecchini G, Tridente G, Marchisio PC.Thymocyte contact or monoclonal antibody-mediated clustering of 3beta1 or 6beta4 integrins activate interleukin-6 (IL-6) transcription factors (NF-kappaB and NF-IL6) and IL-6 production in human thymic epithelial cells.Blood.10,3745-55.
29. Zahir N, Lakins JN, Russell A, Ming W, Chatterjee C, Rozenberg GI, Marinkovich MP, Weaver VM.Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.J Cell Biol.6,1397-407.
30. Hamelers IH, Olivo C, Mertens AE, Pegtel DM, van der Kammen RA, Sonnenberg A, Collard JG.The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration.J Cell Biol. 5,871-81.
31. Dans M, Gagnoux-Palacios L, Blaikie P, Klein S, Mariotti A, Giancotti FG.Tyrosine phosphorylation of the beta 4 integrin cytoplasmic domain mediates Shc signaling to extracellular signal-regulated kinase and antagonizes formation of hemidesmosomes.J Biol Chem. 2,1494-502.
32. Mainiero F, Murgia C, Wary KK, Curatola AM, Pepe A, Blumemberg M, Westwick JK, Der CJ, Giancotti FG.The coupling of alpha6beta4 integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation.EMBO J.9,2365-75.
33. Mainiero F, Pepe A, Wary KK, Spinardi L, Mohammadi M, Schlessinger J, Giancotti FG.Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes.EMBO J. 18,4470-81.
34. Mainiero F, Pepe A, Yeon M, Ren Y, Giancotti FG.The intracellular functions of alpha6beta4 integrin are regulated by EGF.J Cell Biol.1,241-53.