RESEARCH SUMMARY:
The areas of research in this laboratory
are: 1) autocrine transformation by the v-sis/c-sis oncogene
and novel trans-Golgi network (TGN) signal transduction, and
2) role of the transforming growth factor ß (TGF-ß) type V receptor
(TR-V) in the biological functions of TGF-ß.
1) Autocrine transformation by the v-sis/c-sis oncogene
and novel TGN signal transduction. For the last two decades,
we have been investigating the mechanism of autocrine transformation
by the growth factor oncogenes (v-sis/c-sis). Autocrine transformation
by the v-sis/c-sis gene product involves the activation of
the platelet-derived growth factor (PDGF) ß-type receptor
by the v-sis/c-sis gene product during routing of both ligand
(v-sis/c-sis gene product) and the receptor from the ER, Golgi
complex to plasma membranes or extracellular compartments.
We have recently found that persistent signal transduction
mediated by this PDGF ß-type receptors activated at the TGN
plays a critical role in autocrine transformation of the cells.
We are currently investigating the mechanisms of the novel
TGN signal transduction using transfection and gene knockout
approaches.
2) Role of the TGF ß-type V receptor (TR-V) in the biological
functions of TGF. The type V- ß TGF receptor (TR-V) is a 400-kDa
non-proteoglycan membrane glycoprotein which was first identified
in our laboratory. It is a Ser-specific protein kinase and
co-expresses with type I, type II, and type III TGF-receptors
(TR-I, TR-II, and TR-III) in most cell types. However, the
selective absence of the TR-V in most epithelial tumor cells
studied suggests that TR-V is a candidate tumor suppressor
gene product. We recently made the novel observation that
TR-V is the receptor for insulin-like growth factor binding
proteins-3, -4, and -5 (IGFBP-3, -4, and -5) which mediate
the IGF-independent growth inhibitory response induced by
these IGFBPs. Most recently, we have found that the signaling
mediated by TR-V does not involve the stimulated phosphorylation
of Smad2/Smad3, critical signaling transducers of the TR-I/TR-II
heterocomplex. The goals of this research project are to determine
the mechanism of the TR-V-mediated growth inhibitory response
and to test the hypothesis that TR-V is the product of a tumor
suppressor gene.
Figure: A model for reversal of IGFBP-3 and TGF-ß
growth inhibition by insulin or IGF-I and for cross talk of
the TßR-I/TßR-II, TßR-V (or TßR-V/TßR-I),
insulin receptor, IGF-I receptor, integrin and c-Met signaling
cascades
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