PROLACTIN ACTIVATES RAS VIA SIGNALLING PROTEINS SHC, GRB2 AND SOS
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Date
1995-05
Type of Work
Department
Hood College Biology
Program
Biomedical and Environmental Science
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Abstract
Identification of the signal transduction pathways used
by prolactin (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 JAK and SRC families, with rapid
nuclear signalling via tyrosine phosphorylated STAT
transcription factors. In the present study we provide the
first demonstration of PRL-induced activation of RAS, an
oncogenic protein that supports a separate signalling route
from the membrane to the nucleus. In rat Nb2-SP lymphoma
cells PRL stimulated RAS as detected by a 2.0-fold increase
in the GTP-bound state of the molecule (p<0.01). RAS
activation was associated with marked tyrosine phosphorylation
and increased membrane association of the 52 kDa
form of SHC. PRL induced binding of SHC to GRB2 and the
guanine-nucleotide exchange factor SOS, 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-GTPase-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 the subsequent stimulation
of the serine/threonine kinase RAF-1, an established RAStarget
that was recently shown to be activated by PRL in
Nb2 cells. In conclusion, PRL is able to activate RAS via
recruitment of the signaling proteins SHC, GRB2 and SOS in
Nb2 cells. Moreover, prolactin induced tyrosine phosphorylation
of SHC in two out of three PRL-responsive human
breast cancer cell lines, suggesting that SHC-mediated RAS
activation is a commonly used signalling strategy for PRL.