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Fibronectin shown to colocalize with fibrillar actin. Proposed a transmembrane relationship between microfilaments and FN Anchorage dependence defined 1964 1968 Addition of fibronectin to tumor cells induces cell flattening and reorganization of the actin cytoskeleton 1977 Mammary epithelial cells could be induced to produce milk proteins when cultured on floating collagen gels Receptors for matrix proteins purified First evidence of vSrc localization to focal adhesions 1978 1979 First full length b subunit and partial a subunit cDNAs cloned RGD defined as the minimal cell binding motif of ECMs 1984 1980 First evidence of affinity modulation of matrix receptors Phosphotyrosine is detected in focal adhesions The shape of adherent cells found to be a critical determinant of cell proliferation 1985 1986 Evidence that affinity modulation of integrins involves conformational changes b1 integrin shown to colocalize with extracellular focal adhesions and intracellular cytoskeletal components Talin shown to associate with b1. Demonstrated physical association of cytoskeletal protein with integrin b2 integrin deficiency in humans results in impaired immune function aIIbb3 integrin mutations in platelets responsible for Glanzmann thrombasthenia Integrins and Fc receptors cooperate in induction of oxidative burst in neutrophils a6b4 localizes to hemidesmosomes Antibodies to b1 block differentiation of myoblasts 1987 FAK is cloned and shown to be 120kD protein that is tyrosine phosphorylated after attachment of cells to integrins Integrins control induction of tyrosine phosphorylation 1988 Integrin adhesion induces transcription of cellular genes b2 integrins also undergo affinity modulation 1989 Na-H antiporters, which regulate intracellular pH, were found to be regulated by integrins PKC found to localize to FA 1990 Epithelial and endothelial cells require attachment to matrix for survival 1992 1991 1993 Rho, Rac and Cdc42 regulate the production of focal adhesions/stress fibers and lamellipodia Cytoplasmic tails of integrins regulate affinity for ligand Engagement of integrins strongly enhances TCR response Attachment to matrix induces Erk activation 1994 Adhesion required for cyclinA induction by growth factors b1 integrin engagement controls the differentiation of keratinocytes Casein production in mammary epithelial cells requires proper matrix attachment Integrin a subunits interact with caveolin and transduce signals to Erk through Fyn and Shc b1 integrin knock-out demonstrates role of integrins in mammalian development 1995 FAK knock-out demonstrates the involvement of FAK in focal adhesion turnover 1996 Pathway from Cas to Crk to DOCK180 to Rac identified EGFR and b1 exert recipricol effects on transformed cells in normal 3D organization 1997 Prolonged activation of Erk by growth factors requires integrin adhesion Integrins transactivate growth factor receptors Cyclin D induction and p21/p27 downregulation by growth factors requires matrix attachment Identification of a novel integrin induced pathway that regulates the Rho family GEF, Vav 1998 Adhesion is sufficient for induction of lamellipodia, filopodia and focal adhesion formation 1999 Integrin activation of Rac is required for cyclin D translation and progression through G1 2000 2001 Adhesion to matrix activates Rho and Rac Syndecans cooperative with integrins in focal adhesion formation 3D matrices induce formation of novel focal adhesion structures not detected when cells are grown on immobilized martrix