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Substrate Profiling of Protein Tyrosine Phosphatases

Award Number: R01CA132855
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2008
PERIOD OF PERFORMANCE END DATE: 11/30/2013

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Substrate Profiling of Protein Tyrosine Phosphatases - DESCRIPTION (provided by applicant): Reversible phosphorylation of proteins on tyrosine controls the execution and regulation of many cellular processes. A proper level of tyrosyl phosphorylation is critical for these processes and is controlled by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). A large number of PTPs (>100) have been identified and their importance in physiological and pathological processes has been demonstrated unambiguously. However, their mechanisms of action in these processes remain unclear. To understand their mechanisms of action, a critical first step is to identify their protein substrates involved in these processes, a currently very challenge task. This project describes the development and application of a chemical/bioinformatics approach to the identification of PTP substrates. In this approach, the substrate specificity of PTP is systematically determined by screening a combinatorial peptide library and the consensus motif(s) is used to search protein and genomic databases to identify potential protein substrates. The candidate proteins are subsequently validated as genuine PTP substrates (or rejected as false positives) by conventional cellular assays. In this project, we will focus our studies on three classical, non-receptor PTPs: the prototypical PTP1B and two Src homology 2 (SH2) domain-containing PTPs, SHP-1 and SHP-2. It consists of three specific aims. Specific Aim 1 is to further develop the combinatorial peptide library method and determine the substrate specificity of PTP1B, SHP-1, and SHP-2. Specific Aim 2 is to identify the in vivo protein substrates of PTP1B, SHP-1, and SHP-2. Specific Aim 3 is to characterize SHP-2 mutants that are involved in human diseases. The binding and substrate specificity of the SH2 and PTP domains in SHP-2 mutants will be determined and the resulting information will be utilized to identify any protein substrates abnormally acted upon by SHP-2 mutants. PUBLIC HEALTH RELEVANCE: PTPs play critical roles in both physiological and pathological processes and are therefore an important class of targets for chemotherapeutic intervention. PTP1B is currently being pursued as a target for treatment of type 2 diabetes. Mutations in SHP-2 cause Noonan syndrome, LEOPARD syndrome, and several leukemias. Catalytically defective SHP-1 mutants cause motheaten mice, which have a dysregulated immune system and die prematurely of inflammatory syndrome 2-3 weeks after birth. This project will investigate the molecular mechanisms by which these three PTPs function in physiological and pathological processes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	5	11/6/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $243,854 )
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	5	11/27/2012	NON-COMPETING CONTINUATION	$129,710
2013	2013	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	001	5	5/9/2013	NON-COMPETING CONTINUATION	$114,144
														Subtotal = $243,854

Issue Date FY: 2012 ( Subtotal = $259,419 )
2012	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	001	4	4/30/2012	NON-COMPETING CONTINUATION	$25,942
2012	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	4	11/17/2011	NON-COMPETING CONTINUATION	$233,477
														Subtotal = $259,419

Issue Date FY: 2011 ( Subtotal = $259,419 )
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	001	3	5/12/2011	NON-COMPETING CONTINUATION	$18,721
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	3	10/28/2010	NON-COMPETING CONTINUATION	$240,698
														Subtotal = $259,419

Issue Date FY: 2010 ( Subtotal = $277,877 )
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	003	2	4/8/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$26,816
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	002	2	11/27/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$241,344
2010	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	1	11/25/2009	NEW	$0
2010	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	001	1	11/25/2009	NEW	$9,717
														Subtotal = $277,877

Issue Date FY: 2009 ( Subtotal = $268,837 )
2009	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	001	1	3/20/2009	NEW	$9,717
2009	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	1	11/27/2008	NEW	$259,120
														Subtotal = $268,837

Grand Total All Awards = $1,309,406

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Substrate Profiling of Protein Tyrosine Phosphatases

Award Number: R01CA132855

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2008

PERIOD OF PERFORMANCE END DATE: 11/30/2013

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