The role of ACK in regulating the Vav family proteins

The non-receptor tyrosine kinase effector of Cdc42, ACK, has been identified as an oncogene. Aberrant expression and mutations of ACK have been found in many types of cancer, such as prostate, breast and pancreatic. Clinically, ACK mutants or overexpression correlates with poor prognosis. Recent studies have uncovered substrates for ACK and shown their downstream signalling pathways can contribute to cancer progression. However, whether ACK can be used as a therapeutic target in cancer remains a debatable issue. It is likely that the ACK signalling network is yet to be completely elucidated. To understand whether ACK is an effective, as well as a safe target for cancer therapy, the Owen/Mott group performed a yeast-2-hybrid screen to identify new binding partners of ACK. 14 novel proteins that interact with ACK were identified, one of which was a small G protein regulator Vav3, the least-studied member of Vav-family proteins. The first part of this project characterised the interactions between ACK and Vav-family proteins in human cells. ACK was shown not only to bind to Vav3, but also to Vav1 and Vav2. From mutagenesis studies, it was shown that ACK binds Vav2 differently to Vav1 and Vav3. Further experiments indicated that the interaction with Vav1 and Vav3 stabilized ACK protein levels, an outcome that could underpin the oncogenic properties of ACK and the situation found in many cancers. For Vav2, it was shown that ACK phosphorylates Tyr142 and directs Vav2 GEF activity towards the small G protein Cdc42, resulting in an increase of HEK293T cell proliferation. Knockdown of Vav2 significantly reduced the level of activated Cdc42 and decreased the proliferative rate in ACK-transformed cells. Finally, the ACK-Vav2-Cdc42 pathway was shown to promote cell migration in an androgen-independent prostate cancer cell line. Taken together, this project has identified a new potential player in ACK-driven oncogenesis.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Ip, Chi Yeung Marco

Advisor dc:contributor.advisor

• Owen, Darerca

• ACK kinase
• Cdc42
• Small G proteins
• Small GTPases
• Vav family proteins

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.94117

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/346697