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Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression.

ABSTRACT: Autoinhibition of the Rho guanine nucleotide exchange factor ASEF is relieved by interaction with the APC tumor suppressor. Here we show that binding of the armadillo repeats of APC to a 'core APC-binding' (CAB) motif within ASEF, or truncation of the SH3 domain of ASEF, relieves autoinhibition, allowing the specific activation of CDC42. Structural determination of autoinhibited ASEF reveals that the SH3 domain forms an extensive interface with the catalytic DH and PH domains to obstruct binding and activation of CDC42, and the CAB motif is positioned adjacent to the SH3 domain to facilitate activation by APC. In colorectal cancer cell lines, full-length, but not truncated, APC activates CDC42 in an ASEF-dependent manner to suppress anchorage-independent growth. We therefore propose a model in which ASEF acts as a tumor suppressor when activated by APC and inactivation of ASEF by mutation or APC truncation promotes tumorigenesis.

SUBMITTER: Mitin N

PROVIDER: S-EPMC2716141 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression.

Mitin Natalia N Betts Laurie L Yohe Marielle E ME Der Channing J CJ Sondek John J Rossman Kent L KL

Nature structural & molecular biology 20070819 9

Autoinhibition of the Rho guanine nucleotide exchange factor ASEF is relieved by interaction with the APC tumor suppressor. Here we show that binding of the armadillo repeats of APC to a 'core APC-binding' (CAB) motif within ASEF, or truncation of the SH3 domain of ASEF, relieves autoinhibition, allowing the specific activation of CDC42. Structural determination of autoinhibited ASEF reveals that the SH3 domain forms an extensive interface with the catalytic DH and PH domains to obstruct binding ...[more]

PMID: 17704816

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Project description:IntroductionAlthough intratumoral chemoablation can obtain an impressive therapeutic effect, there is still incomplete ablation and tumor recurrence in some patients. This could be due to the short retention time of the drug in the tumor, the limited distribution of intratumoral drugs, and, beyond that, the immunotolerance caused by the tumor microenvironment (TME). There is still an urgent need to find an optimal drug sustained-release carrier and figure out the impact of regional injection to TME.MethodsIn this study, we supposed to use polyethylene glycol (PEG) hydrogel as a drug carrier to improve the retention time of the drug to extend the exposure of tumor cells and investigate the feasibility of combination local Epirubicin injection with anti-PD-L1.ResultsThe results revealed obvious tumor suppression based on the tumor volume and the inhibition time of tumor growth in the A549 lung cancer mouse model after local injection. Furthermore, the enhanced antitumor effects of the combination of systematic anti- programmed death ligand 1 (PD-L1) therapy with local chemoablation (EPI-GEL/PD-L1) for abscopal tumor reduction in the 4T1 breast model were also observed. Flow cytometry analysis of the tumor and blood samples showed significant variations in the proportions of PD-L1+ and CD3+CD8+PD-1+ cells before and after anti-PD-L1 therapy. On day 4 after local injection of the EPI gel, the expression of PD-L1 in abscopal tumors was upregulated, while the expression of PD-L1 in bilateral tumors in mice was significantly reduced after anti-PD-L1 treatment. The proportion of CD3+CD8+PD-1+ cells in the tumor and circulating blood in the EPI-GEL/PD-L1 group was decreased compared with that in the EPI-GEL (single injection of epirubicin) group.DiscussionThe combination of local injection of the chemoablation agent with anti-PD-L1 monoclonal antibody (mAb) therapy may strengthen the antitumor activity, and the use of PEG hydrogel as the drug carrier can extend the retention time of the chemoablation agent around the tumor, maintaining a long-term tumor-killing activity.

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Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression.

Publications

Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression.

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