Research Papers:

SCFβ-TRCP targets MTSS1 for ubiquitination-mediated destruction to regulate cancer cell proliferation and migration

Jiateng Zhong, Shavali Shaik, Lixin Wan, Adriana E. Tron, Zhiwei Wang, Liankun Sun, Hiroyuki Inuzuka and Wenyi Wei _

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Oncotarget. 2013; 4:2339-2353. https://doi.org/10.18632/oncotarget.1446

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Jiateng Zhong1,2,*, Shavali Shaik1,*, Lixin Wan1, Adriana E. Tron1, Zhiwei Wang1, Liankun Sun2, Hiroyuki Inuzuka1 and Wenyi Wei1

1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

2 Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Changchun, P. R. China

* These two authors contributed equally to this work


Hiroyuki Inuzuka, email:


Wenyi Wei, email:

Keywords: tumor suppressor, MTSS1, ubiquitination, phosphorylation, migration

Received: September 25, 2013 Accepted: November 4, 2013 Published: November 6, 2013


Metastasis suppressor 1 (MTSS1) is an important tumor suppressor protein, and loss of MTSS1 expression has been observed in several types of human cancers. Importantly, decreased MTSS1 expression is associated with more aggressive forms of breast and prostate cancers, and with poor survival rate. Currently, it remains unclear how MTSS1 is regulated in cancer cells, and whether reduced MTSS1 expression contributes to elevated cancer cell proliferation and migration. Here we report that the SCFβ-TRCP regulates MTSS1 protein stability by targeting it for ubiquitination and subsequent destruction via the 26S proteasome. Notably, depletion of either Cullin 1 or β-TRCP1 led to increased levels of MTSS1. We further demonstrated a crucial role for Ser322 in the DSGXXS degron of MTSS1 in governing SCFβ-TRCP-mediated MTSS1 degradation. Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1’s interaction with β-TRCP for subsequent ubiquitination and degradation. Importantly, introducing wild-type MTSS1 or a non-degradable MTSS1 (S322A) into breast or prostate cancer cells with low MTSS1 expression significantly inhibited cellular proliferation and migration. Moreover, S322A-MTSS1 exhibited stronger effects in inhibiting cell proliferation and migration when compared to ectopic expression of wild-type MTSS1. Therefore, our study provides a novel molecular mechanism for the negative regulation of MTSS1 by β-TRCP in cancer cells. It further suggests that preventing MTSS1 degradation could be a possible novel strategy for clinical treatment of more aggressive breast and prostate cancers.

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