A central question to be addressed in cell regulation is the biochemical mechanism by which many different kinds of signaling proteins and enzymes work in concert to mediate cellular responses to a specific extracellular stimulus. We are just beginning to appreciate that scaffold or adapter proteins may play important roles in signal relay from the plasma membrane to intracellular targets by aggregating a variety of proteins into specific signaling pathways or networks. We and others have recently identified a novel human scaffold protein, Gab2, that is closely related to Gab I (Grb2-associated binder 1) and Drosophila Dos (daughter of sevenless). Both Gabi and Gab2 contain a PH domain and mutliple potential tyrosine phosphorylation sites for SH2 proteins as well as proline-rich motifs for SH3 binding. Interestingly, we have found that Gabi and Gab2 exhibit reciprocal functions in coupling cytoplasmic-nuclear signaling, and that Gab2 acts to suppress the activity of the transcription factor Elk-i induced by oncogenic RasV 12 or epidermal growth factor, without down-regulating extracellular signal-regulated kinase (Erk) activity. We hypothesize that Gab2 acts to aggregate a unique set of enzymes and their specific substrates for signal relay, which represents a novel and unexplored pathway in intracellular signaling. The goal of this proposal is to dissect this pathway for the negative effect of Gab2 in signal transduction. This will be accomplished by: 1). identification of the structural domain in Gab2 involved in the negative regulatory role; 2). isolation and functional analysis of proteins that interact with Gab2 through the """"""""negative effect domain""""""""; 3). elucidation of the physiological consequence of the Gab2 interaction with its partners; and 4). determination of the biological function of Gab2 in vivo by generating a Gab2-deficient mouse model. This work will enable us to understand better the mechanism whereby the specificity of intracellular signaling is achieved through organization of multimolecular complexes (signalsomes) by scaffold proteins, such as Gab2, and will also aid in designing efficient pharmaceutical intervention of certain cellular disorders associated with heart failure, diabetes and malignant diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066208-04
Application #
6682326
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Buxton, Denis B
Project Start
2001-01-01
Project End
2005-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$438,750
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Ke, Y; Wu, D; Princen, F et al. (2007) Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene 26:4951-60
Teal, H E; Ni, S; Xu, J et al. (2006) GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of Friend virus-infected erythroid progenitor cells. Oncogene 25:2433-43
Sun, Yingqing; Yuan, Jing; Liu, Houqi et al. (2004) Role of Gab1 in UV-induced c-Jun NH2-terminal kinase activation and cell apoptosis. Mol Cell Biol 24:1531-9
Zhao, Chunmei; Ma, Hong; Bossy-Wetzel, Ella et al. (2003) GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2. J Biol Chem 278:34641-53
Shen, Randy; Ouyang, Ying-Bin; Qu, Cheng-Kui et al. (2002) Grap negatively regulates T-cell receptor-elicited lymphocyte proliferation and interleukin-2 induction. Mol Cell Biol 22:3230-6