title: A laminin-collagen complex drives human epidermal carcinogenesis through phosphoinositol-3-kinase activation.
abstract: Laminin-332 (formerly laminin-5) and collagen VII are basement membrane proteins expressed at the invasive front of human squamous cell carcinoma (SCC) tumors. These proteins have protumorigenic properties, but whether laminin-332 and collagen VII promote SCC tumors by providing adhesion or other nonadhesive extracellular cues, or whether laminin-332 and collagen VII interact together in this process remains unknown. In this study, we examined the role of these molecules by a structural approach using an in vivo model of human SCC tumorigenesis. Here, we show that individual domains (VI and V-III) on the laminin-332 beta3 chain provide distinct and highly divergent cell adhesion and tumor-promoting functions. We found that laminin beta3 domain VI provided a critical role in the assembly of stable adhesion complexes, but this domain was not required in SCC tumors. Instead, we found that laminin beta3 domain V-III played an essential role in SCC carcinogenesis/invasion through binding to collagen VII, which in turn, led to phosphoinositol-3-kinase activation and protection from apoptosis. Overexpression of constitutively active p110 phosphoinositol-3-kinase subunit was sufficient to restore invasion and tumorigenesis in transformed cells lacking laminin-332/collagen VII interaction in a manner independent of cellular adhesion. These studies show distinctive adhesive and signaling functions in individual domains of laminin-332, one which is required for normal epithelial adhesion and one which is required for SCC tumorigenesis. This uncoupling of stable adhesion from tumor progression in our studies suggests that laminin-332/collagen VII interaction promotes epidermal carcinogenesis through signaling rather than adhesion.
authors.affiliation: Dermatology Service, Palo Alto VAHCS, Palo Alto, California 94305, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Waterman
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Sakai
authors.forename: Ngon T
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Basil A J
authors.initials: BA
authors.lastname: Horst
authors.forename: Dallas P
authors.initials: DP
authors.lastname: Veitch
authors.forename: Clara N
authors.initials: CN
authors.lastname: Dey
authors.forename: Susana
authors.initials: S
authors.lastname: Ortiz-Urda
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
authors.forename: M Peter
authors.initials: MP
authors.lastname: Marinkovich
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D024143:Collagen Type VII / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D024143:Collagen Type VII; D019869:Phosphatidylinositol 3-Kinases; D000097794:Kalinin