A role for Src in signal relay by the platelet-derived growth factor α receptor
A role for Src in signal relay by the platelet-derived growth factor α receptor
复制标题
DOI：
10.1074/jbc.273.10.5908
复制
发表时间：
1998-03-06
影响因子：
4.8
通讯作者：
Kazlauskas, A
中科院分区：
文献类型：
--
作者：
Gelderloos, JA;Rosenkranz, S;Kazlauskas, A
先前的研究表明，Src是成纤维细胞中血小板衍生生长因子（PDGF）依赖性细胞周期进展所必需的。由于成纤维细胞通常表达两种PDGF受体（pdgfb），这些发现表明Src tva对于α和β pdgfr的信号传递是必需的。在本研究中，我们重点研究了Src在α PDGFR信号传递中的作用。PDGF-AA选择性地参与α - PDGFR，作为对PDGF-AA刺激的响应，与α - PDGFR和Src激酶相关的Src家族成员（Src）被激活，一种突变受体，其中酪氨酸572和574被苯丙氨酸（F72/74）取代，不能有效地与Src结合或激活Src。野生型（WT）和F72/74受体诱导c-myc和c-fos的表达达到相当水平。此外，在表达F72/74 α PDGFR WT的细胞中观察到相同程度的pdgf依赖性软琼脂生长。比较这两种受体启动信号分子酪氨酸磷酸化的能力表明，这两种受体介导受体本身、磷脂酶C γ 1和SHP-2的磷酸化水平相似。相比之下，F72/74受体分别触发55- kda和46-kDa Shc亚型的Shc磷酸化至WT水平的1和20%。这些发现表明，在细胞暴露于PDGF-AA后，Src稳定地与α PDGFR结合，并且Src活性增加。此外，Src是信号分子如She的pdgf依赖性磷酸化所必需的。最后，在G(0)/G(1)转换过程中，Src的激活似乎并不需要后一个细胞。周期事件，如诱导c-myc或细胞增殖。
Previous studies have shown that Src is required for platelet-derived growth factor (PDGF)-dependent cell cycle progression in fibroblasts. Since fibroblasts usually express both PDGF receptors (PDGFBs), these findings suggested that Src Tvas mandatory for signal relay by both the alpha and beta PDGFRs. In this study, we have focused on the role of Src in signal relay by the alpha PDGFR. In response to stimulation with PDGF-AA, which selectively engages the alpha PDGFR, Src family members (Src) associated with the alpha PDGFR and Src kinase were activated, A mutant receptor, in which tyrosines 572 and 574 were replaced with phenylalanine (F72/74), failed to efficiently associate with Src or activate Src. The wild type (WT) and F72/74 receptors induced the expression of c-myc and c-fos to comparable levels. Furthermore, an equivalent extent of PDGF-dependent soft agar growth was observed in cells expressing the WT of the F72/74 alpha PDGFR. Comparing the ability of these two receptors to initiate tyrosine phosphorylation of signaling molecules indicated that both receptors mediated phosphorylation of the receptor itself, phospholipase C gamma 1, and SHP-2 to similar levels. In contrast, the F72/74 receptor triggered phosphorylation of Shc to 1 and 20% of the WT levels for the 55- and 46-kDa Shc isoforms, respectively, These findings indicate that after exposure of cells to PDGF-AA, Src stably associates with the alpha PDGFR, and Src activity-is increased. Furthermore, Src is required for the PDGF-dependent phosphorylation of signaling molecules such as She. Finally, activation of Src during the G(0)/G(1) transition does not appear to be required for latter cell. cycle events such as induction of c-myc or cell proliferation.