First name
Martina
Last name
Zobel
Year of Study
Research Center
Thesis Title
Spatial regulation of signalling by the endocytic protein NUMB
Thesis Abstract
NUMB is a cell fate determinant that controls signaling outputs during asymmetric cell division. NUMB is a tumor suppressor protein which regulates NOTCH and p53 signalling pathways. Its loss occurs in 50% of all breast tumors and 30% of lung cancers and correlates with increase aggressiveness and poor prognosis. NUMB binds to key players of Clathrin-mediated endocytosis, regulating the internalization of various receptors and it has been found to localize in recycling endosomes where it may regulate the delivery of cargos back to the plasma membrane (PM).
We found that NUMB is as a negative regulator of Circular Dorsal Ruffles (CDRs) formation downstream of c-MET and PDGFR. This is accompanied by an increased mesenchymal mode of motility and cell invasion. CDRs formation depends on the recycling back of active RAC to spatial restricted sites of PM via ARF6. We found that NUMB is enriched in ARF6 recycling compartments and inhibits MHC I and RAC recycling. These evidences suggest that NUMB might act as a negative regulator of ARF6-dependent recycling. We found that among the ARF6 GEFs, only EFA6B contains an NPxF motif in its N-terminal domain and directly binds the NUMB PTB domain. Functionally, the removal of EFA6B by itself does not alter CDR formation, but it inhibits the increase of CDR formation that is brought about by NUMB down-regulation.
Our data suggest that NUMB may regulate the ARF6-dependent recycling pathway, which is required for migration and invasion of tumor cells, by interacting with and possibly modulating its GEF EFA6B.
We found that NUMB is as a negative regulator of Circular Dorsal Ruffles (CDRs) formation downstream of c-MET and PDGFR. This is accompanied by an increased mesenchymal mode of motility and cell invasion. CDRs formation depends on the recycling back of active RAC to spatial restricted sites of PM via ARF6. We found that NUMB is enriched in ARF6 recycling compartments and inhibits MHC I and RAC recycling. These evidences suggest that NUMB might act as a negative regulator of ARF6-dependent recycling. We found that among the ARF6 GEFs, only EFA6B contains an NPxF motif in its N-terminal domain and directly binds the NUMB PTB domain. Functionally, the removal of EFA6B by itself does not alter CDR formation, but it inhibits the increase of CDR formation that is brought about by NUMB down-regulation.
Our data suggest that NUMB may regulate the ARF6-dependent recycling pathway, which is required for migration and invasion of tumor cells, by interacting with and possibly modulating its GEF EFA6B.
Students representatives
Off
Curricula Term