RASSF1A directly antagonizes RhoA activity through the assembly of a Smurf1-mediated destruction complex to suppress tumorigenesis

Min Goo Lee, Seong In Jeong, Kyung Phil Ko, Soon Ki Park, Byung Kyu Ryu, Ick Young Kim, Jeong Kook Kim, Sung-Gil Chi

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

RASSF1A is a tumor suppressor implicated inmany tumorigenic processes;however, the basis for its tumor suppressor functions are not fully understood. Here we show that RASSF1A is a novel antagonist of protumorigenic RhoA activity. Direct interaction between the C-terminal amino acids (256-277) of RASSF1A and active GTP-RhoA was critical for this antagonism. In addition, interaction between the N-terminal amino acids (69-82) of RASSF1A and the ubiquitin E3 ligase Smad ubiquitination regulatory factor 1 (Smurf1) disrupted GTPase activity by facilitating Smurf1-mediated ubiquitination of GTP-RhoA. We noted that the RhoA-binding domain of RASSF1A displayed high sequence homology with Rho-binding motifs in other RhoA effectors, such as Rhotekin. As predicted on this basis, RASSF1A competed with Rhotekin to bind RhoA and to block its activation. RASSF1A mutants unable to bind RhoA or Smurf1 failed to suppress RhoA-induced tumor cell proliferation, drug resistance, epithelial-mesenchymal transition, migration, invasion, and metastasis. Clinically, expression levels of RASSF1A and RhoA were inversely correlated in many types of primary and metastatic tumors and tumor cell lines. Collectively, our findings showed how RASSF1A may suppress tumorigenesis by intrinsically inhibiting the tumorpromoting activity of RhoA, thereby illuminating the potential mechanistic consequences of RASSF1A inactivation in many cancers.

Original languageEnglish
Pages (from-to)1847-1859
Number of pages13
JournalCancer Research
Volume76
Issue number7
DOIs
Publication statusPublished - 2016 Apr 1

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Ubiquitination
Carcinogenesis
Neoplasms
Guanosine Triphosphate
Amino Acids
Ubiquitin-Protein Ligases
Epithelial-Mesenchymal Transition
GTP Phosphohydrolases
Sequence Homology
Tumor Cell Line
Drug Resistance
Cell Proliferation
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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RASSF1A directly antagonizes RhoA activity through the assembly of a Smurf1-mediated destruction complex to suppress tumorigenesis. / Lee, Min Goo; Jeong, Seong In; Ko, Kyung Phil; Park, Soon Ki; Ryu, Byung Kyu; Kim, Ick Young; Kim, Jeong Kook; Chi, Sung-Gil.

In: Cancer Research, Vol. 76, No. 7, 01.04.2016, p. 1847-1859.

Research output: Contribution to journalArticle

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