Document Detail


Prolactin activates Ras via signaling proteins SHC, growth factor receptor bound 2, and son of sevenless.
MedLine Citation:
PMID:  7628388     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Identification of the signal transduction pathways used by PRL is essential for understanding the role of PRL receptors in growth and differentiation processes. Early cellular mediators of PRL receptor activation include tyrosine kinases of the Janus kinase (JAK) and SRC families, with rapid nuclear signaling via tyrosine phosphorylated signal transducers and activators of transcription. In the present study we provide the first demonstration of PRL-induced activation of Ras, an oncogenic protein that supports an alternative signaling route from the membrane to the nucleus. PRL stimulated Ras in rat Nb2-SP lymphoma cells, as detected by a 2.0-fold increase in the GTP-bound state of the molecule (P < 0.01). This activation was associated with marked tyrosine phosphorylation and increased membrane association of the 52-kilodalton form of SHC. Moreover, PRL induced binding of SHC to growth factor receptor bound 2 and the guanine-nucleotide exchange factor son of sevenless, a common method used by growth factor receptors to activate Ras. In contrast, no apparent regulation by PRL of Ras via VAV or p120 Ras-guanosine triphosphatase-activating protein was detected, based upon an absence of PRL-inducible tyrosine phosphorylation of these proteins. Collectively, these results provide a molecular bridge between activation of PRL receptor-associated tyrosine kinases and subsequent stimulation of the serine/threonine kinase Raf-1, an established Ras target that was recently shown to be activated by PRL in Nb2 cells. We conclude that PRL is able to activate Ras via recruitment of the signaling proteins SHC, growth factor receptor bound 2, and son of sevenless in Nb2 cells. Moreover, PRL induced tyrosine phosphorylation of SHC in two of three PRL-responsive human breast cancer cell lines, suggesting that SHC-mediated Ras activation is a commonly used signaling strategy by PRL.
Authors:
R A Erwin; R A Kirken; M G Malabarba; W L Farrar; H Rui
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Endocrinology     Volume:  136     ISSN:  0013-7227     ISO Abbreviation:  Endocrinology     Publication Date:  1995 Aug 
Date Detail:
Created Date:  1995-09-01     Completed Date:  1995-09-01     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3512-8     Citation Subset:  AIM; IM    
Affiliation:
Biological Carcinogenesis and Development Program, Program Resources, Inc./DynCorp, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing*
Animals
GRB2 Adaptor Protein
Gene Expression Regulation / drug effects*
Genes, ras / drug effects*
Humans
Membrane Proteins / physiology*
Prolactin / pharmacology*
Protein Sorting Signals / physiology
Proteins / physiology*
Rats
Sheep
Son of Sevenless Proteins
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/GRB2 Adaptor Protein; 0/GRB2 protein, human; 0/Grb2 protein, rat; 0/Membrane Proteins; 0/Protein Sorting Signals; 0/Proteins; 0/Son of Sevenless Proteins; 9002-62-4/Prolactin

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