Blume-Jensen P, Janknecht R, Hunter T
Molecular Biology and Virology Laboratory, Salk Institute, La Jolla, California 92037, USA.
Curr Biol. 1998 Jun 18;8(13):779-82. doi: 10.1016/s0960-9822(98)70302-1.
The c-kit-encoded receptor protein tyrosine kinase for stem cell factor (Kit/SCF-R) is essential for the development of cells within the hematopoietic, melanogenic and gametogenic lineages. SCF stimulation induces activation of phosphatidylinositol (PI) 3-kinase, which is required for SCF-induced mitogenesis and cell survival, and for activation of the serine/threonine, we found that, in response to SCF Akt became activated and mediated phosphorylation of Bad, a pro-apoptotic molecule, in a PI-3-kinase-dependent manner. Phosphorylation of Bad was restricted to Ser112 and Ser136 in vivo, but only the Akt phosphorylation sit Ser136 was essential for SCF-promoted cell survival. Furthermore, Bad and Akt interacted and colocalized in intact cells. A Kit/SCF-R gain-of-function mutant that has increased mitogenic and PI 3-kinase activation potential, due to the absence of the two protein kinase C negative feedback phosphorylation site, enhanced both Akt activation and Bad phosphorylation and also resulted in increased cell survival. Such a mechanism may account for how deregulated PI 3-kinase activity and naturally occurring gain-of-function point mutants of Kit/SCF-R lead to cellular transformation and fatal malignancies in man.
干细胞因子的c-kit编码受体蛋白酪氨酸激酶（Kit/SCF-R）对于造血、黑素生成和配子生成谱系中的细胞发育至关重要。SCF刺激诱导磷脂酰肌醇（PI）3激酶的激活，这是SCF诱导的有丝分裂和细胞存活以及丝氨酸/苏氨酸激活所必需的。我们发现，响应SCF时，Akt被激活并以PI-3激酶依赖的方式介导促凋亡分子Bad的磷酸化。Bad的磷酸化在体内限于Ser112和Ser136，但只有Akt磷酸化位点Ser136对SCF促进的细胞存活至关重要。此外，Bad和Akt在完整细胞中相互作用并共定位。由于缺少两个蛋白激酶C负反馈磷酸化位点而具有增加的有丝分裂和PI 3激酶激活潜能的Kit/SCF-R功能获得性突变体增强了Akt激活和Bad磷酸化，也导致细胞存活增加。这样一种机制可能解释了PI 3激酶活性失调以及Kit/SCF-R的自然发生的功能获得性点突变如何导致人类细胞转化和致命恶性肿瘤。
