title: P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at 5 threonine sites promotes cell transformation.
abstract: The oncoprotein c-Jun is one of the components of the activator protein-1 (AP-1) transcription factor complex. AP-1 regulates the expression of many genes and is involved in a variety of biological functions such as cell transformation, proliferation, differentiation and apoptosis. AP-1 activates a variety of tumor-related genes and therefore promotes tumorigenesis and malignant transformation. Here, we found that epidermal growth factor (EGF) induces phosphorylation of c-Jun by P21-activated kinase (PAK) 2. Our data showed that PAK2 binds and phosphorylates c-Jun at five threonine sites (Thr2, Thr8, Thr89, Thr93 and Thr286) in vitro and ex vivo. Knockdown of PAK2 in JB6 Cl41 (P+) cells had no effect on c-Jun phosphorylation at Ser63 or Ser73 but resulted in decreases in EGF-induced anchorage-independent cell transformation, proliferation and AP-1 activity. Mutation at all five c-Jun threonine sites phosphorylated by PAK2 decreased the transforming ability of JB6 cells. Knockdown of PAK2 in SK-MEL-5 melanoma cells also decreased colony formation, proliferation and AP-1 activity. These results indicated that PAK2/c-Jun signaling plays an important role in EGF-induced cell proliferation and transformation.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue North East, Austin, MN 55912, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Jishuai
authors.initials: J
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Weihong
authors.initials: W
authors.lastname: Wen
authors.forename: Tatyana
authors.initials: T
authors.lastname: Zykova
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Cong
authors.initials: C
authors.lastname: Peng
authors.forename: Weiya
authors.initials: W
authors.lastname: Ma
authors.forename: Guozheng
authors.initials: G
authors.lastname: Shi
authors.forename: Ziming
authors.initials: Z
authors.lastname: Dong
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013912:Threonine / Q000378:metabolism*; D046888:Tissue Array Analysis; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D013912:Threonine; D004815:Epidermal Growth Factor; D054462:p21-Activated Kinases