Kostic Ana, Sheetz Michael P
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Mol Biol Cell. 2006 Jun;17(6):2684-95. doi: 10.1091/mbc.e05-12-1161. Epub 2006 Apr 5.
Cell motility on extracellular matrices critically depends on matrix rigidity, which affects cell adhesion and formation of focal contacts. Receptor-like protein tyrosine phosphatase alpha (RPTPalpha) and the alphavbeta3 integrin form a rigidity-responsive complex at the leading edge. Here we show that the rigidity response through increased spreading and growth correlates with leading edge recruitment of Fyn, but not endogenous c-Src. Recruitment of Fyn requires the palmitoylation site near the N-terminus and addition of that site to c-Src enables it to support a rigidity response. In all cases, the rigidity response correlates with the recruitment of the Src family kinase to early adhesions. The stretch-activated substrate of Fyn and c-Src, p130Cas, is also required for a rigidity response and it is phosphorylated at the leading edge in a Fyn-dependent process. A possible mechanism for the fibronectin rigidity response involves force-dependent Fyn phosphorylation of p130Cas with rigidity-dependent displacement. With the greater displacement of Fyn from p130Cas on softer surfaces, there will be less phosphorylation. These studies emphasize the importance of force and nanometer-level movements in cell growth and function.
细胞在细胞外基质上的运动性严重依赖于基质硬度，而基质硬度会影响细胞黏附以及黏着斑的形成。受体样蛋白酪氨酸磷酸酶α（RPTPα）和αvβ3整合素在细胞前沿形成一个硬度响应复合物。在此我们表明，通过增加铺展和生长实现的硬度响应与Fyn在前缘的募集相关，但与内源性c-Src无关。Fyn的募集需要靠近N端的棕榈酰化位点，将该位点添加到c-Src上可使其支持硬度响应。在所有情况下，硬度响应都与Src家族激酶募集到早期黏附位点相关。Fyn和c-Src的伸展激活底物p130Cas对于硬度响应也是必需的，并且它在前沿以Fyn依赖的过程被磷酸化。纤连蛋白硬度响应的一种可能机制涉及p130Cas的力依赖型Fyn磷酸化以及硬度依赖型位移。在较软表面上Fyn与p130Cas的位移更大，磷酸化程度就会更低。这些研究强调了力和纳米级运动在细胞生长和功能中的重要性。
