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66
hRME-6, a rab5GEF that integrates endocytosis and
signalling
Emma Maxwell 1 , Marie Marron 1 .
University of Sheffield 1
Abstract:
Rab5 is a major regulator of the early endocytic pathway, modulating transport vesicle
formation, endosomal fusion and motility, and signalling. A key question is how rab5 is spatially
and temporally regulated on the endocytic pathway. Emerging evidence suggests that rab5
guanine nucleotide exchange factors (GEFs) are key to the establishment of functional pools of
rab5 and our lab has demonstrated how the plasma membrane rab5GEF, hRME-6, establishes a
functional pool of rab5 that regulates uncoating of AP2 from clathrin-coated vesicles. An
emerging paradigm in intracellular signalling is that, contrary to what was previously thought,
signalling receptors can signal throughout the endocytic pathway and, importantly, signalling
output may be different depending on the localisation of the signalling molecule. This suggests a
tight coupling between endocytosis and signalling. In addition to its Vps9 domain that is
essential for GEF activity, hRME-6 has a rasGAP domain at its N-terminus suggesting that it is a
good candidate to integrate endocytic trafficking with intracellular signalling. We have explored
this possibility by analysis of trafficking and signalling of the Tie2 receptor tyrosine kinase in
endothelial cells. Our results indicate that hRME-6 can specifically modulate Tie2 signalling and
support a model whereby hRME-6 can establish a Tie2 ‘signalosome’.