Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Sci Rep. 2016 Jul 1;6:28687. doi: 10.1038/srep28687.
Monocyte chemotactic protein 1 (MCP1) stimulates phosphorylation of cortactin on Y421 and Y446 residues in a time-dependent manner and phosphorylation at Y446 but not Y421 residue is required for MCP1-induced CDK-interacting protein 1 (p21Cip1) nuclear export and degradation in facilitating human aortic smooth muscle cell (HASMC) proliferation. In addition, MCP1-induced cortactin tyrosine phosphorylation, p21Cip1 degradation and HASMC proliferation are dependent on Fyn activation. Upstream to Fyn, MCP1 stimulated C-C chemokine receptor type 2 (CCR2) and Gi/o and inhibition of either one of these molecules using their specific antagonists or inhibitors attenuated MCP1-induced cortactin tyrosine phosphorylation, p21Cip1 degradation and HASMC proliferation. Cortactin phosphorylation at Y446 residue is also required for another G protein-coupled receptor (GPCR) agonist, thrombin-induced p21Cip1 nuclear export and its degradation in promoting HASMC proliferation. Quite interestingly, the receptor tyrosine kinase (RTK) agonist, platelet-derived growth factor-BB (PDGF-BB)-induced p21Cip1 degradation and HASMC proliferation do not require cortactin tyrosine phosphorylation. Together, these findings demonstrate that tyrosine phosphorylation of cortactin at Y446 residue is selective for only GPCR but not RTK agonist-induced nuclear export and proteolytic degradation of p21Cip1 in HASMC proliferation.
单核细胞趋化蛋白 1（MCP1）可时间依赖性地刺激皮质蛋白 Y421 和 Y446 残基的磷酸化，而 Y446 残基的磷酸化而不是 Y421 残基的磷酸化对于 MCP1 诱导的 CDK 相互作用蛋白 1（p21Cip1）核输出和降解是必需的，以促进人主动脉平滑肌细胞（HASMC）增殖。此外，MCP1 诱导的皮质蛋白酪氨酸磷酸化、p21Cip1 降解和 HASMC 增殖依赖于 Fyn 的激活。在 Fyn 上游，MCP1 刺激 C-C 趋化因子受体 2（CCR2）和 Gi/o，使用它们的特异性拮抗剂或抑制剂抑制其中任何一种分子均可减弱 MCP1 诱导的皮质蛋白酪氨酸磷酸化、p21Cip1 降解和 HASMC 增殖。皮质蛋白 Y446 残基的磷酸化对于另一种 G 蛋白偶联受体（GPCR）激动剂，凝血酶诱导的 p21Cip1 核输出及其降解在促进 HASMC 增殖中也是必需的。有趣的是，受体酪氨酸激酶（RTK）激动剂血小板衍生生长因子-BB（PDGF-BB）诱导的 p21Cip1 降解和 HASMC 增殖不需要皮质蛋白酪氨酸磷酸化。总之，这些发现表明，皮质蛋白 Y446 残基的酪氨酸磷酸化仅选择性地用于 GPCR 激动剂，而不是 RTK 激动剂诱导的 HASMC 增殖中的 p21Cip1 核输出和蛋白水解降解。
