The death effector domain of PEA-15 is involved in its regulation of integrin activation.
Increased integrin ligand binding affinity (activation) is triggered by intracellular signaling events. A Ras-initiated mitogen-activated protein kinase pathway suppresses integrin activation in fibroblasts. We used expression cloning to isolate cDNAs that prevent Ras suppression of integrin activation. Here, we report that PEA-15, a small death effector domain (DED)-containing protein, blocks Ras suppression. PEA-15 does not block the capacity of Ras to activate the ERK mitogen-activated protein kinase pathway. Instead, it inhibits suppression via a pathway blocked by a dominant-negative form of the distinct small GTPase, R-Ras. Heretofore, all known DEDs functioned in the regulation of apoptosis. In contrast, the DED of PEA-15 is essential for its capacity to reverse suppression of integrin activation. Thus, certain DED-containing proteins can regulate integrin activation as opposed to apoptotic protease cascades.
Ramos
J W
JW
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Kojima
T K
TK
Hughes
P E
PE
Fenczik
C A
CA
Ginsberg
M H
MH
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D016023:Integrins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D018631:ras Proteins