Vav1, an oncogene and a signal transducer protein
My research focuses on discovering the links between the signaling pathways
within cells and the transforming processes that cause cancer. Cell behavior,
including growth, survival and motility, is regulated by a complex network of
intracellular and extracellular signal transduction pathways. There is great
interest in identifying and characterizing the components of these signaling
pathways, and learning how they go awry in disease states. Cancer is often
associated with mis-regulated signal transduction, frequently stemming from
mutated versions of normal (onco)genes and tumor suppressor genes. It is
therefore critical to learn more about the normal and abnormal function of these
signal transduction molecules.
Vav1 is one
important example of a signal transducer protein involved in cancer. While
working in Dr Mariano Barbacid’s laboratory, I identified Vav1 in a screen for
oncogenes in which NIH3T3 cells were transfected with DNA from several
esophageal carcinomas. Nucleotide sequence analysis revealed that the Vav
oncogene was activated in vitro. Since Vav was the sixth oncogene detected in
Dr. Barbacid's laboratory it was designated Vav, the sixth letter of the Hebrew
alphabet.
I subsequently identified its wild-type form, now termed Vav1. It is
now clear that Vav1 is an important signal transducer with a pivotal role in the
hematopoietic system, in which it is exclusively expressed. My research has made
a major contribution to the identification, characterization and understanding
of the physiological role of Vav1 in hematopoietic cells. Elimination of Vav1 in
the mouse genome leads to faulty functions and impaired development of the
immune system, highlighting its physiological importance. I have shown that Vav1
encodes a unique protein with several modular motifs known to play a role in
tyrosine mediated signal transduction. Activation of Vav1 leads to cytoskeletal
rearrangement during activation of hematopoietic cells, an event critical for
numerous cell functions.
Until recently, the Vav1 oncogene had not been detected in human
cancer. Thus, although truncated versions of Vav1 lacking the amino terminus
transform NIH3T3 fibroblasts and synergize with active Ras in transformation,
their role in human tumorigenesis was disputed. My laboratory was the first to
demonstrate that ectopic expression of wild-type Vav1, not its mutant form, is
involved in human malignancies, strongly suggesting that Vav1 contributes to the
neoplastic process in a subset of neuroblastomas. We have since demonstrated
that Vav1 is involved in human lung cancer, a malignancy which is the leading
cause of cancer death worldwide, as well as in human breast cancer.
Our results suggest that Vav1
plays a role in the neoplastic processes, identifying it as a potential
therapeutic target for cancer therapy.
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Knock-down of Vav1 in Cancer Cells Inhibits
Tumor Progression and Restores Normal Cytoskeleton Organization.
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