|
Nicholas
A. Cacalano, PhD
Assistant professor
B.S. Cornell University 1985
M.Phil Columbia University 1988
PhD Columbia University 1992
Postdoc UCSF/DNAX Research Institute
My
laboratory is interested in the molecular mechanisms of cytokine and growth
factor receptor signal transduction, and understanding how deregulated
signaling results in human diseases such as Severe Combined Immunodeficiency
(SCID) and cancer.
Cytokines
are alpha-helical polypeptide growth factors that stimulate the growth,
proliferation, and survival of cells from all tissues and organs. Cytokines
mediate their biological effects through specific cell surface receptors
that transduce biochemical signals which modulate cytokine-specific gene
expression. Signal transduction by cytokine receptors is accomplished
through their non-covalent association with cytoplasmic tyrosine kinases
of the Janus (Jak) family. This interaction is critical for the activation
of cytokine-specific genetic programs as well as cellular proliferation
and survival. My laboratory studies signaling through the receptor for
interleukin-2, an essential T cell growth factor which regulates immune
responses. The IL-2 receptor is a heterotrimeric receptor complex of which
two components, the beta and gamma (gc) chains associate with the Janus
kinases Jak1 and Jak3, respectively. The role of the gamma chain and Jak3
in signal transduction through this receptor has been demonstrated by
the identification of human patients lacking either gc or Jak3 who suffer
from SCID. We have recently identified a Jak3 point mutation in a human
SCID patient that disrupts kinase-receptor interaction and abolishes gc-dependent
signal transduction. We mapped the receptor binding site to the N-terminal
256 amino acids of Jak3 and determined that this domain associates with
a proline-rich, membrane-proximal sequence of gc. We are presently in
the process of producing purified receptor-binding fragments of Jak3 for
x-ray crystallographic analysis, and generating mutants of Jak3 to study
intramolecular interactions that regulate kinase activity and subcellular
localization.
My
lab is also interested in the mechanisms that control and negatively regulate
cytokine signal transduction. Recently, we have identified a novel family
of inhibitors, the Suppressors of Cytokine Signaling (SOCS) as key regulators
of cytokine receptor activity. We demonstrated that one member of this
superfamily, SOCS3, inhibits IL-2-mediated responses by modulating the
activation of the STAT5 transcription factor. We have also made the novel
observation that SOCS3 is tyrosine phosphorylated by Jak and receptor
tyrosine kinases and binds to the ras inhibitor p120 RasGAP, as well as
the Nck and Crk-L adaptor molecules in a phosphotyrosine-dependent manner.
We have shown that SOCS3 inhibits RasGAP activity and maintains the activation
of the ras pathway in response to cytokine and growth factor stimulation.
Thus, SOCS3 functions as a pathway-specific molecular switch that inhibits
a subset of cytokine-activated signaling modules (STATs), but ensures
cell survival by maintaining the activity of the ras-dependent MAP kinase
pathway. My lab is presently in the process of determining the biological
function of the SOCS3-Nck and SOCS3-Crk-L interactions, as well as the
role of SOCS3 in T helper cell development and its possible function as
a tumor suppressor.
|
