The RIN1 protein is a RAS effector expressed predominantly in mature forebrain neurons. RIN1 stimulates ABL family tyrosine kinases and directs cytoskeletal remodeling. RIN1 null mutant mice show a striking increase in long term potentiation (LTP) and enhancement in memory (i.e. RIN1 normally inhibits learning). H-,K-, NRAS and ABL2 are also expressed in forebrain neurons and perform learning and memory functions. These studies provide critical insights into a tissue-specific RAS pathway that regulates neuronal plasticity (learning). Understanding RIN1 function may also have implications for neuropsychiatric disorders. RIN1 binds to ABL proteins. Moreover, RIN1 is unique as a direct ABL kinase activator. RAS appears to stimulate RIN1 activation of ABL2 and these three proteins (RAS, RIN1, ABL2) are found as a complex in vivo. These data demonstrate a physical and functional connection between RAS and ABL proteins. RIN1 promotes the ABL2 phosphorylation of CRKII and CRKL, adaptor proteins that coordinate cytoskeletal remodeling.
The first aim of this proposal is to define the mechanism by which RIN1 stimulates ABL2 kinase activity. This may involve a substrate-specific enhancement (i.e. RIN1 provides a docking site for CRK proteins) or an allosteric function (i.e., RIN1 induces changes in the ABL2 kinase active site). Understanding the RIN1- mediated stimulation mechanism should expand opportunities for manipulating ABL function in learning, as well as in cell transformation.
The second aim i s to define signaling components used by RIN1 to promote cytoskeletal remodeling. RIN1 and ABL2 are complexed with CRKL in vivo. CRKII and CRKL reorganize the cytoskeleton through multiple SH2 and SH3 binding partners. Identification of RIN1/CRK(L) complex components will provide new insights into stimulus-induced and cell type specific remodeling.
The third aim of this proposal is to evaluate the contribution of RIN1 to neuronal plasticity. RIN1 can coordinate cytoskeletal remodeling as well as compete with other RAS effectors. We will use cultured neurons and brain tissue to determine how neuronal stimulation engages the RAS-RIN1-ABL2-CRK(L) pathway and how activation of this pathway negatively regulates plasticity. Special focus will be placed on dendritic spine remodeling because the connection of this phenomenon to learning remains conjectural. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS046787-01
Application #
6681142
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Babcock, Debra J
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$285,703
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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