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MECHANISM OF RAF-1 ACTIVATION

Award Number: R01GM057959
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1998
PERIOD OF PERFORMANCE END DATE: 01/31/2009

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MECHANISM OF RAF-1 ACTIVATION - DESCRIPTION (provided by applicant): The overall objective of this proposal is to continue to test our hypothesis that activation of Raf-1 kinase requires ordered and cooperative actions of multiple factors including kinases and scaffold proteins. Raf family members are major downstream effectors of Ras and key enzymes in the regulation of cell metabolism, proliferation, differentiation and apoptosis. The Raf kinases are also important factors in neoplasia. Thus, activating mutations of the Ras gene are found in approximately 30% of human cancers and many non-nuclear oncogenes exploit the Ras/Raf/MEK/Erk pathway to execute their oncogenic programs. Previous studies by others and us have demonstrated that different inputs lead to the phosphorylation of S338, which is necessary, but not sufficient for Raf-1 activation. Our preliminary data suggest that S338 is autophosphorylated in response to growth factors (e.g., EGF or TPA), and that it is phosphorylated by Pak in response to microtubule depolymerizing agents such as nocodazole. We have identified several novel phosphorylation sites (e.g. S357) on Raf-1 that appear to participate in its regulation. In addition, we have found that Raf-1 is constitutively activated in the HCT116 colon cancer cell that contains an activating mutation of KiRas. We have also found that suppression of KSR expression by RNAi results in inhibition of Raf/MEK interaction and MEK activation, leading to DNA fragmentation. Finally, our preliminary results indicate that the HCT116 cell extract contains component(s) that allows Raf-1 activation in vitro. Based on these findings, we are proposing studies with the following specific aims: (1) to examine further how S338 is phosphorylated under different conditions and its relationship with other phosphorylation events; (2) to examine the mechanism(s) responsible for the phosphorylation of S357 and to determine the impact of this phosphorylation on Raf function and vRas-mediated transformation (malignancy); and (3) to elucidate the mechanism(s) by which Raf-1 is regulated by KSR in HCT116 cells and to use these cells as a tool to identify novel upstream regulators of Raf-1. These studies will provide new information as to how Raf is activated and how its activation affects cellular functions. They will also serve as a framework for evaluating the role of the Raf family in human malignancy.


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: 2008 ( Subtotal = $277,343 )
2008	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	10	2/20/2008	NON-COMPETING CONTINUATION	$277,343
														Subtotal = $277,343

Issue Date FY: 2007 ( Subtotal = $277,343 )
2007	2007	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	9	3/2/2007	NON-COMPETING CONTINUATION	$277,343
														Subtotal = $277,343

Issue Date FY: 2006 ( Subtotal = $282,990 )
2006	2006	BOSTON MEDICAL CENTER	ONE BOSTON MEDICAL CENTER PL	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	7	1/26/2006	NON-COMPETING CONTINUATION	$282,990
														Subtotal = $282,990

Issue Date FY: 2005 ( Subtotal = $273,368 )
2005	2005	BOSTON MEDICAL CENTER	ONE BOSTON MEDICAL CENTER PL	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	6	2/18/2005	COMPETING CONTINUATION	$273,368
														Subtotal = $273,368

Issue Date FY: 2002 ( Subtotal = $215,980 )
2002	2002	BOSTON MEDICAL CENTER	818 HARRISON AVE, ADMIN BLDG	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	5	9/5/2002	NON-COMPETING CONTINUATION	$215,980
														Subtotal = $215,980

Issue Date FY: 2001 ( Subtotal = $210,375 )
2001	2001	BOSTON MEDICAL CENTER	818 HARRISON AVE, ADMIN BLDG	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	4	8/20/2001	NON-COMPETING CONTINUATION	$210,375
														Subtotal = $210,375

Issue Date FY: 2000 ( Subtotal = $205,708 )
2000	2000	BOSTON MEDICAL CENTER	ONE BOSTON MEDICAL CENTER PL	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	3	9/15/2000	NON-COMPETING CONTINUATION	$205,708
														Subtotal = $205,708

Issue Date FY: 1999 ( Subtotal = $201,158 )
1999	1999	BOSTON MEDICAL CENTER	ONE BOSTON MEDICAL CENTER PL	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	2	8/12/1999	NON-COMPETING CONTINUATION	$201,158
														Subtotal = $201,158

Issue Date FY: 1998 ( Subtotal = $182,619 )
1998	1998	BOSTON MEDICAL CENTER	ONE BOSTON MEDICAL CENTER PL	BOSTON	MA	02118	SUFFOLK	USA	Biomedical Research and Research Training	000	1	7/24/1998	NEW	$182,619
														Subtotal = $182,619

Grand Total All Awards = $2,126,884

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MECHANISM OF RAF-1 ACTIVATION

Award Number: R01GM057959

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1998

PERIOD OF PERFORMANCE END DATE: 01/31/2009

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