Rap1 is involved in cell stretching modulation of p38 but not ERK or JNK MAP kinase.
Mechanical force or mechanical stress modulates intracellular signal pathways, including the mitogen-activated protein kinase (MAP kinase) cascades. In our system, cell stretching activated and cell contraction inactivated all three MAP kinase pathways (MKK1/2-extracellular signal-regulated kinase (ERK), MKK4 (SEK1)-cJun N-terminal kinase (JNK) and MKK3/6-p38 pathways). However, little is known about the molecular mechanisms that link the mechanical force to the MAP kinase cascades. To test whether Ras and Rap1 are possible components in the stretch-activated MAP kinase pathways, we examined if Ras and Rap1 were activated by cell stretching and if inhibition of their activity decreased the stretch-enhanced MAP kinase activity. Rap1 was activated by cell stretching and inactivated by cell contraction, whereas Ras was inactivated by cell stretching and activated by cell contraction. Rap1GapII and SPA-1, downregulators of Rap1 activity, decreased the stretch-enhanced p38 activity, whereas a dominant-negative mutant of Ras (RasN17) did not inhibit the stretch-initiated activation of MAP kinases. Furthermore, overexpression of Rap1 enhanced p38 activity but not ERK or JNK activity. These results indicate that Rap1 is involved in transducing the stretch-initiated signal to the MKK3/6-p38 pathway, but not to the MEK1/2-ERK or the MKK4 (SEK1)/MKK7-JNK pathway. Thus, Rap1 plays a unique role in force-initiated signal transduction.
Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan. ys454@columbia.edu
Y
Y
Sawada
K
K
Nakamura
K
K
Doi
K
K
Takeda
K
K
Tobiume
M
M
Saitoh
K
K
Morita
I
I
Komuro
K
K
De Vos
M
M
Sheetz
H
H
Ichijo
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; C482125:MAP2K1 protein, human; C482530:MAP2K3 protein, human; C482559:MAP2K4 protein, human; C482566:MAP2K6 protein, human; C482569:MAP2K7 protein, human; C482127:Map2k1 protein, mouse; C482531:Map2k3 protein, mouse; C482562:Map2k4 protein, mouse; C482567:Map2k6 protein, mouse; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins