Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding

被引:38
作者
Ting, Pamela Y. [1 ]
Johnson, Christian W. [2 ]
Fang, Cong [3 ,4 ]
Cao, Xiaoqing [1 ]
Graeber, Thomas G. [3 ,4 ]
Mattos, Carla [2 ]
Colicelli, John [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Mol Biol Inst,Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
[2] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA
[3] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Crump Inst Mol Imaging, Metabol & Prote Ctr,Calif Nanosyst Inst, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
GTPase; signal transduction; RIN1; RAF1; NUCLEOTIDE EXCHANGE FACTOR; K-RAS; GTPASE ACTIVITY; BCR-ABL; RIN1; PROTEIN; ACTIVATION; PROMOTES; KINASES; SWITCH;
D O I
10.1096/fj.15-271510
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
RAS proteins are signal transduction gatekeepers that mediate cell growth, survival, and differentiation through interactions with multiple effector proteins. The RAS effector RAS- and RAB-interacting protein 1 (RIN1) activates its own downstream effectors, the small GTPase RAB5 and the tyrosine kinase Abelson tyrosine-protein kinase (ABL), to modulate endocytosis and cytoskeleton remodeling. To identify ABL substrates downstream of RAS-to-RIN1 signaling, we examined human HEK293T cells over-expressing components of this pathway. Proteomic analysis revealed several novel phosphotyrosine peptides, including Harvey rat sarcoma oncogene (HRAS)-pTyr(137). Here we report that ABL phosphorylates tyrosine 137 of H-, K-, and NRAS. Increased RIN1 levels enhanced HRAS-Tyr(137) phosphorylation by nearly 5-fold, suggesting that RAS-stimulated RIN1 can drive ABL-mediated RAS modification in a feedback circuit. Tyr(137) is well conserved among RAS orthologs and is part of a transprotein H-bond network. Crystal structures of HRAS(Y137F) and HRAS(Y137E) revealed conformation changes radiating from the mutated residue. Although consistent with Tyr(137) participation in allosteric control of HRAS function, the mutations did not alter intrinsic GTP hydrolysis rates in vitro. HRAS-Tyr(137) phosphorylation enhanced HRAS signaling capacity in cells, however, as reflected by a 4-fold increase in the association of phosphorylated HRAS(G12V) with its effector protein RAF proto-oncogene serine/threonine protein kinase 1 (RAF1). These data suggest that RAS phosphorylation at Tyr(137) allosterically alters protein conformation and effector binding, providing a mechanism for effector-initiated modulation of RAS signaling.
引用
收藏
页码:3750 / 3761
页数:12
相关论文
共 61 条
  • [11] Allosteric Modulation of Ras-GTP Is Linked to Signal Transduction through RAF Kinase
    Buhrman, Greg
    Kumar, V. S. Senthil
    Cirit, Murat
    Haugh, Jason M.
    Mattos, Carla
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (05) : 3323 - 3331
  • [12] Allosteric modulation of Ras positions Q61 for a direct role in catalysis
    Buhrman, Greg
    Holzapfel, Genevieve
    Fetics, Susan
    Mattos, Carla
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (11) : 4931 - 4936
  • [13] Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation
    Bunda, Severa
    Heir, Pardeep
    Srikumar, Tharan
    Cook, Jonathan D.
    Burrell, Kelly
    Kano, Yoshihito
    Lee, Jeffrey E.
    Zadeh, Gelareh
    Raught, Brian
    Ohh, Michael
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (36) : E3785 - E3794
  • [14] DIRECT IDENTIFICATION OF PALMITIC ACID AS THE LIPID ATTACHED TO P21RAS
    BUSS, JE
    SEFTON, BM
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1986, 6 (01) : 116 - 122
  • [15] Enhancement of ABL Kinase Catalytic Efficiency by a Direct Binding Regulator Is Independent of Other Regulatory Mechanisms
    Cao, Xiaoqing
    Tanis, Keith Q.
    Koleske, Anthony J.
    Colicelli, John
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (46) : 31401 - 31407
  • [16] HUMAN SOS1 - A GUANINE-NUCLEOTIDE EXCHANGE FACTOR FOR RAS THAT BINDS TO GRB2
    CHARDIN, P
    CAMONIS, JH
    GALE, NW
    VANAELST, L
    SCHLESSINGER, J
    WIGLER, MH
    BARSAGI, D
    [J]. SCIENCE, 1993, 260 (5112) : 1338 - 1343
  • [17] ABL Tyrosine Kinases: Evolution of Function, Regulation, and Specificity
    Colicelli, John
    [J]. SCIENCE SIGNALING, 2010, 3 (139)
  • [18] Colicelli John, 2004, Sci STKE, V2004, pRE13, DOI 10.1126/stke.2502004re13
  • [19] Dhaka A, 2003, J NEUROSCI, V23, P748
  • [20] Regulated expression of the Ras effector Rin1 in forebrain neurons
    Dzudzor, Bartholomew
    Huynh, Lucia
    Thai, Minh
    Bliss, Joanne M.
    Nagaoka, Yoshiko
    Wang, Ying
    Ch'ng, Toh Hean
    Jiang, Meisheng
    Martin, Kelsey C.
    Colicelli, John
    [J]. MOLECULAR AND CELLULAR NEUROSCIENCE, 2010, 43 (01) : 108 - 116