Phosphorylation of Serine 779 in Fibroblast Growth Factor Receptor 1 and 2 by Protein Kinase Cε Regulates Ras/Mitogen-activated Protein Kinase Signaling and Neuronal Differentiation

被引:14
作者
Lonic, Ana [1 ]
Powell, Jason A. [1 ]
Kong, Yang [1 ]
Thomas, Daniel [1 ]
Holien, Jessica K. [2 ,3 ]
Nhan Truong [1 ]
Parker, Michael W. [2 ,3 ,4 ]
Guthridge, Mark A. [1 ,5 ]
机构
[1] South Australian SA Pathol, Cell Growth & Differentiat Lab, Div Human Immunol, Adelaide, SA 5000, Australia
[2] St Vincents Inst Med Res, Biota Struct Biol Lab, Fitzroy, Vic 3065, Australia
[3] St Vincents Inst Med Res, Australian Canc Res Fund ACRF Rat Drug Discovery, Fitzroy, Vic 3065, Australia
[4] Univ Melbourne, Dept Biochem & Mol Biol, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3052, Australia
[5] Monash Univ, Div Blood Canc, Australian Ctr Blood Dis, Alfred Med Res & Educ Precinct, Melbourne, Vic 3004, Australia
基金
英国医学研究理事会;
关键词
ELIMINATES PHOSPHATIDYLINOSITOL HYDROLYSIS; POINT MUTATION; NEURITE OUTGROWTH; CELL-SURVIVAL; PC12; CELLS; PATHWAYS; PKC; IDENTIFICATION; SPECIFICITY; INDUCTION;
D O I
10.1074/jbc.M112.421669
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The FGF receptors (FGFRs) control a multitude of cellular processes both during development and in the adult through the initiation of signaling cascades that regulate proliferation, survival, and differentiation. Although FGFR tyrosine phosphorylation and the recruitment of Src homology 2 domain proteins have been widely described, we have previously shown that FGFR is also phosphorylated on Ser(779) in response to ligand and binds the 14-3-3 family of phosphoserine/threonine-binding adaptor/scaffold proteins. However, whether this receptor phosphoserine mode of signaling is able to regulate specific signaling pathways and biological responses is unclear. Using PC12 pheochromocytoma cells and primary mouse bone marrow stromal cells as models for growth factor-regulated neuronal differentiation, we show that Ser(779) in the cytoplasmic domains of FGFR1 and FGFR2 is required for the sustained activation of Ras and ERK but not for other FGFR phosphotyrosine pathways. The regulation of Ras and ERK signaling by Ser(779) was critical not only for neuronal differentiation but also for cell survival under limiting growth factor concentrations. PKC epsilon can phosphorylate Ser(779) in vitro, whereas overexpression of PKC epsilon results in constitutive Ser(779) phosphorylation and enhanced PC12 cell differentiation. Furthermore, siRNA knockdown of PKC epsilon reduces both growth factor-induced Ser(779) phosphorylation and neuronal differentiation. Our findings show that in addition to FGFR tyrosine phosphorylation, the phosphorylation of a conserved serine residue, Ser(779), can quantitatively control Ras/MAPK signaling to promote specific cellular responses.
引用
收藏
页码:14874 / 14885
页数:12
相关论文
共 51 条
[1]   The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site [J].
Bae, Jae Hyun ;
Lew, Erin Denise ;
Yuzawa, Satoru ;
Tome, Francisco ;
Lax, Irit ;
Schlessinger, Joseph .
CELL, 2009, 138 (03) :514-524
[2]   The C2 domain of PKCδ is a phosphotyrosine binding domain [J].
Benes, CH ;
Wu, N ;
Elia, AEH ;
Dharia, T ;
Cantley, LC ;
Soltoff, SP .
CELL, 2005, 121 (02) :271-280
[3]  
Brodie C, 1999, CELL GROWTH DIFFER, V10, P183
[4]  
Corbit KC, 1999, MOL CELL BIOL, V19, P4209
[5]   The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells [J].
Cross, MJ ;
Lu, LG ;
Magnusson, P ;
Nyqvist, D ;
Holmqvist, K ;
Welsh, M ;
Claesson-Welsh, L .
MOLECULAR BIOLOGY OF THE CELL, 2002, 13 (08) :2881-2893
[6]   Mechanisms underlying differential responses to FGF signaling [J].
Dailey, L ;
Ambrosetti, D ;
Mansukhani, A ;
Basilico, C .
CYTOKINE & GROWTH FACTOR REVIEWS, 2005, 16 (02) :233-247
[7]   Cellular signaling by fibroblast growth factor receptors [J].
Eswarakumar, VP ;
Lax, I ;
Schlessinger, J .
CYTOKINE & GROWTH FACTOR REVIEWS, 2005, 16 (02) :139-149
[8]   Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes [J].
Fambrough, D ;
McClure, K ;
Kazlauskas, A ;
Lander, ES .
CELL, 1999, 97 (06) :727-741
[9]   The role of tyrosine residues in fibroblast growth factor receptor 1 signaling in PC12 cells - Systematic site-directed mutagenesis in the endodomain [J].
Foehr, ED ;
Raffioni, S ;
Murray-Rust, J ;
Bradshaw, RA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (40) :37529-37536
[10]   Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction [J].
Furdui, CM ;
Lew, ED ;
Schlessinger, J ;
Anderson, KS .
MOLECULAR CELL, 2006, 21 (05) :711-717