Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells

Kug Hwa Lee, Woo Jeong Jeong, Pu Hyeon Cha, Sang Kyu Lee, Do Sik Min, Kang-Yell Choi

Research output: Contribution to journalArticle

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Abstract

Scaffold proteins of the mitogen activated protein kinase (MAPK) pathway recruit protein kinase cascades to confer context-specificity to cellular signaling. Varying concentrations of scaffold proteins determine different aspects of signaling outputs. However, regulatory mechanisms of scaffold proteins are poorly understood. Sur8, a scaffold protein in the Ras-MAPK pathway, is known to be involved in cell transformation and migration, and is increased in human colorectal cancer (CRC) patient tissue. Here we determine that regulation of Sur8 stability mediates transformation and migration of CRC cells. Fibroblast growth factor 2 (FGF2) is identified as an external regulator that stabilizes Sur8. Protein kinase C-alpha and -delta (PKCα/δ) are also identified as specific mediators of FGF2 regulation of Sur8 stability. PKCα/δ phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. Sur8 mutations, which mimic phosphorylation by PKCα/δ and destabilized Sur8, suppress the FGF2-induced transformation and migration of CRC cells. The clinical relevance of Sur8 regulation by PKCα/δ is indicated by the inverse relationship between PKCα/δ and Sur8 expression in human CRC patient tissues. Overall, our findings demonstrate for the first time a regulatory mechanism of Sur8 stability involving cellular transformation and migration in CRC.

Original languageEnglish
Pages (from-to)115596-115608
Number of pages13
JournalOncotarget
Volume8
Issue number70
DOIs
Publication statusPublished - 2017 Jan 1

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Colorectal Neoplasms
Fibroblast Growth Factor 2
Mitogen-Activated Protein Kinases
Phosphorylation
Polyubiquitin
Protein Kinase C-delta
Protein Kinase C-alpha
ras Proteins
Proteins
Protein Kinases
Cell Movement
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lee, Kug Hwa ; Jeong, Woo Jeong ; Cha, Pu Hyeon ; Lee, Sang Kyu ; Min, Do Sik ; Choi, Kang-Yell. / Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells. In: Oncotarget. 2017 ; Vol. 8, No. 70. pp. 115596-115608.
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abstract = "Scaffold proteins of the mitogen activated protein kinase (MAPK) pathway recruit protein kinase cascades to confer context-specificity to cellular signaling. Varying concentrations of scaffold proteins determine different aspects of signaling outputs. However, regulatory mechanisms of scaffold proteins are poorly understood. Sur8, a scaffold protein in the Ras-MAPK pathway, is known to be involved in cell transformation and migration, and is increased in human colorectal cancer (CRC) patient tissue. Here we determine that regulation of Sur8 stability mediates transformation and migration of CRC cells. Fibroblast growth factor 2 (FGF2) is identified as an external regulator that stabilizes Sur8. Protein kinase C-alpha and -delta (PKCα/δ) are also identified as specific mediators of FGF2 regulation of Sur8 stability. PKCα/δ phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. Sur8 mutations, which mimic phosphorylation by PKCα/δ and destabilized Sur8, suppress the FGF2-induced transformation and migration of CRC cells. The clinical relevance of Sur8 regulation by PKCα/δ is indicated by the inverse relationship between PKCα/δ and Sur8 expression in human CRC patient tissues. Overall, our findings demonstrate for the first time a regulatory mechanism of Sur8 stability involving cellular transformation and migration in CRC.",
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Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells. / Lee, Kug Hwa; Jeong, Woo Jeong; Cha, Pu Hyeon; Lee, Sang Kyu; Min, Do Sik; Choi, Kang-Yell.

In: Oncotarget, Vol. 8, No. 70, 01.01.2017, p. 115596-115608.

Research output: Contribution to journalArticle

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