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Wnt
and Hedgehog are secreted growth factors controlling several cellular
processes such as proliferation, differentiation and migration.
Because they control such fundamental cellular functions their signalling
pathways are, perhaps not surprisingly, found to be misregulated
in several human diseases such as cancer.
The first axis
of research in my laboratory aims at understanding the molecular
mechanisms operating in cells to integrate the biological response
activated when Wnt and Hedgehog proteins are recognized by their
cell surface receptors. Using an integrative proteomic approach
combining traditional biochemistry techniques with novel mass spectrometry
tools we are identifying and functionally characterizing novel proteins
participating in the transmission or regulation of the intracellular
signals controlled by these proteins. This work leads to the better
understanding of Wnt and Hedgehog function and help elucidating
the molecular bases of human diseases where these pathways are malfunctioning.
Another area
of research is the study of the Cullin-4 family of E3 ubiquitin
ligases. We recently identified the family of substrate specific
receptors, DCAFs, for the Cullin-4 E3 apparatus. Within E3 ubiquitin
ligase complexes, substrate specific receptors dictate the specificity
for the ubiquitination reaction by selectively recruiting substrates
to the ubiquitin machinery core. Whereas their identity and the
mechanisms by which these substrates are recruited by other Cullin
families (such as the Cullin-1 based SCF complexes) are better characterized,
the Cul-4 family is poorly understood and few substrates have been
identified. Roles for the control of genome integrity and for the
DNA damage response have now been shown for the Cul-4 E3 ligase.
The identification of novel substrates and the characterization
of their regulation by the Cul-4 machinery will identify additional
cellular functions for these ubiquitin ligase complexes.
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| Major,
M. B., Camp, N. D., Berndt, J. D., Yi, X., Goldenberg, S. J., Hubbert,
C., Biechele, T. L., Gingras, A. C., Zheng, N., Maccoss, M. J.,
Angers, S., and Moon, R. T. Wilms Tumor Suppressor WTX Negatively
Regulates WNT/b-catenin Signaling. (2007) Science 316(5827),
1043-1046
Angers, S.,
Thorpe, C. J., Biechele, T. L., Goldenberg, S. J., Zheng, N., MacCoss,
M. J., and Moon, R. T. The KLHL12-Cullin-3 ubiquitin ligase negatively
regulates the Wnt-beta-catenin pathway by targeting Dishevelled
for degradation. (2006) Nat Cell Biol 8(4), 348-357
Angers, S.,
Li, T., Yi, X., MacCoss, M. J., Moon, R. T., and Zheng, N. Molecular
architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery.
(2006) Nature 443(7111), 590-593
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