Tyrosine 1062 of RET-MEN2A mediates activation of Akt (protein kinase B) and mitogen-activated protein kinase pathways leading to PC12 cell survival.
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.
De Vita
G
G
Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Richerche, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Naples, Italy.
Melillo
R M
RM
Carlomagno
F
F
Visconti
R
R
Castellone
M D
MD
Bellacosa
A
A
Billaud
M
M
Fusco
A
A
Tsichlis
P N
PN
Santoro
M
M
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D053938:DNA Fragmentation; D029721:Drosophila Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D020287:In Situ Nick-End Labeling; D008024:Ligands; D020935:MAP Kinase Signaling System; D009025:Morpholines / Q000494:pharmacology; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
D002867:Chromones; D016895:Culture Media, Serum-Free; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D014443:Tyrosine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C416649:Ret protein, Drosophila; C495001:Ret protein, rat; C494920:Akt1 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one