Abstract
Serotonin (5-HT) is a potent mitogen in many cells types, an action which is frequently mediated through pertussis toxin-sensitive G proteins. In the current study, we used pharmacological inhibitors and dominant negative signaling constructs to delineate elements which participate in the activation of MAPK, a growth-associated mitogen-activated protein kinase, by human G protein-coupled 5-HT1A receptor transfected into CHO-K1 cells in a stable manner. The activation pathway does not directly involve phorbol ester-sensitive protein kinase C types, but does require (i) pertussis toxin-sensitive G protein beta gamma-subunits, (ii) a staurosporine- and genistein-sensitive protein kinase, (iii) phosphoinositide-3'-kinase activity, (iv) activation of Sos in a multimolecular complex that contains p46Shc, and p52Shc, and Grb2, (v) the GTPase p21Ras, and (vi) the protein kinase p74Raf-1. These data demonstrate that the 5-HT1A receptor mediates MAPK activity by convergence upon a common activation pathway that is shared with receptor tyrosine kinases.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Adaptor Proteins, Vesicular Transport*
-
Animals
-
CHO Cells
-
Calcium-Calmodulin-Dependent Protein Kinases / immunology
-
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
-
Cricetinae
-
Enzyme Activation / drug effects
-
GRB2 Adaptor Protein
-
GTP-Binding Proteins / metabolism*
-
Gene Expression Regulation / genetics
-
Immunoblotting
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases*
-
Pertussis Toxin
-
Precipitin Tests
-
Protein-Tyrosine Kinases / immunology
-
Protein-Tyrosine Kinases / metabolism
-
Proteins / metabolism
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Receptors, Serotonin / genetics
-
Receptors, Serotonin / metabolism*
-
Receptors, Serotonin, 5-HT1
-
Shc Signaling Adaptor Proteins
-
Signal Transduction / physiology
-
Src Homology 2 Domain-Containing, Transforming Protein 1
-
Transfection / genetics
-
Virulence Factors, Bordetella / pharmacology
Substances
-
Adaptor Proteins, Signal Transducing
-
Adaptor Proteins, Vesicular Transport
-
GRB2 Adaptor Protein
-
Proteins
-
Receptors, Serotonin
-
Receptors, Serotonin, 5-HT1
-
SHC1 protein, human
-
Shc Signaling Adaptor Proteins
-
Src Homology 2 Domain-Containing, Transforming Protein 1
-
Virulence Factors, Bordetella
-
Pertussis Toxin
-
Protein-Tyrosine Kinases
-
Receptor Protein-Tyrosine Kinases
-
Calcium-Calmodulin-Dependent Protein Kinases
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Mitogen-Activated Protein Kinases
-
GTP-Binding Proteins