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In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild\u2010type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild\u2010type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT\/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first\u2010line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild\u2010type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug\u2010resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.<\/jats:p>","DOI":"10.1002\/mc.23727","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T10:38:28Z","timestamp":1713350308000},"page":"1334-1348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling"],"prefix":"10.1002","volume":"63","author":[{"given":"Shaoting","family":"Zhang","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medical Sciences Ningxia Medical University Yinchuan 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