De Vita G, Melillo R M, Carlomagno F, Visconti R, Castellone M D, Bellacosa A, Billaud M, Fusco A, Tsichlis P N, Santoro M
Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Richerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Naples, Italy.
Cancer Res. 2000 Jul 15;60(14):3727-31.
The RET tyrosine kinase is a functional receptor for neurotrophic ligands of the glial cell line-derived neurotrophic factor (GDNF) family. Loss of function of RET is associated with congenital megacolon or Hirschsprung's disease, whereas germ-line point mutations causing RET activation are responsible for multiple endocrine neoplasia type 2 (MEN2A, MEN2B, and familial medullary thyroid carcinoma) syndromes. Here we show that the expression of a constitutively active RET-MEN2A oncogene promotes survival of rat pheochromocytoma PC12 cells upon growth factor withdrawal. Moreover, we show that the RET-MEN2A-mediated survival depends on signals transduced by the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. Thus, in PC12 cells, RET-MEN2A associates with the PI3K regulatory subunit p85 and promotes activation of Akt (also referred to as protein kinase B) in a PI3K-dependent fashion; in addition, RET-MEN2A promotes MAPK activation. PI3K recruitment and Akt activation as well as MAPK activation depend on RET-MEN2A tyrosine residue 1062. As a result, tyrosine 1062 of RET-MEN2A is essential for RET-MEN2A-mediated survival of PC12 cells cultured in growth factor-depleted media.
RET 酪氨酸激酶是胶质细胞系衍生神经营养因子（GDNF）家族神经营养配体的功能性受体。RET功能丧失与先天性巨结肠或赫希施普龙病相关，而导致RET激活的种系点突变则是造成2型多发性内分泌肿瘤（MEN2A、MEN2B和家族性甲状腺髓样癌）综合征的原因。在此我们表明，组成型活性RET-MEN2A癌基因的表达在生长因子撤除后可促进大鼠嗜铬细胞瘤PC12细胞的存活。此外，我们还表明，RET-MEN2A介导的存活依赖于磷脂酰肌醇3激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）级联传导的信号。因此，在PC12细胞中，RET-MEN2A与PI3K调节亚基p85结合，并以PI3K依赖的方式促进Akt（也称为蛋白激酶B）的激活；此外，RET-MEN2A促进MAPK激活。PI3K募集、Akt激活以及MAPK激活均依赖于RET-MEN2A的酪氨酸残基1062。因此，RET-MEN2A的酪氨酸1062对于在生长因子缺乏培养基中培养的PC12细胞的RET-MEN2A介导的存活至关重要。
