Localized Stabilization of Microtubules by Integrin- and FAK-Facilitated Rho Signaling

Abstract

Microtubule (MT) stabilization is regulated by the small guanosine triphosphate (GTP)-binding protein Rho and its effector, mammalian homolog of Diaphanous (mDia), in migrating cells, but factors responsible for localized stabilization at the leading edge are unknown. We report that integrin-mediated activation of focal adhesion kinase (FAK) at the leading edge is required for MT stabilization by the Rho-mDia signaling pathway in mouse fibroblasts. MT stabilization also involved FAK-regulated localization of a lipid raft marker, ganglioside GM1, to the leading edge. The integrin-FAK signaling pathway may facilitate Rho-mDia signaling through GM1, or through a specialized membrane domain containing GM1, to stabilize MTs in the leading edge of migrating cells.

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…Src [200], FAK and MEKK1 [193] appear to regulate calpain activity in part through ERK phosphorylation of the protease [96,192]. FAK null cells exhibit less stable microtubules [201], lower calpain activity [193], decreased ERK signaling [198,202,203] and reduced migratory potential due to defects in focal adhesion disassembly [86], consistent with the view that signaling from FAK to ERK may alter migratory responses through ERK stimulated calpain proteolysis of focal adhesion components and actin remodeling, and microtubule dynamics.…”

In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

“…It is known that Src family proteins are located in GEM [49] with CD44 enrichment in GEM [21] possibly being due to its constitutive association with lck [24]. CD49d ligation induces FAK phosphorylation, which creates docking sites for SH2 and SH3 domain containing proteins [50]. Thus, CD44 and CD49d could associate with each other via adapter or signal transducing molecules.…”

“…Since Rac activation is also required for CD44 polarization [21], CD49d-associated CD44 may become recruited into temporally and spatially regulated signaling complexes [55] that allow its contribution to directed cell migration. Again, the GEM association of CD44 could be important for microtubule stabilization at the leading edge that requires GM1 or GM1-containing membrane domains [50].…”

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

“…This model of FAK activation and Tyr-397 phosphorylation is thought to be of central importance for FAKdependent signaling. The biological importance of FAK-mediated signal transduction is underscored by the fact that this tyrosine kinase plays a fundamental role in embryonic development [11,12] and in the control of cell migration [9,[12][13][14][15][16][17][18][19], cell cycle progression [20] and apoptosis [21][22][23][24]. Furthermore, there is increasing evidence linking overexpression of FAK to the invasive properties of cancer cells [25][26][27][28][29][30][31].…”