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タイトル
  • en Substrate recognition by Arg/Pro‐rich insert domain in calcium/calmodulin‐dependent protein kinase kinase for target protein kinases
作成者
    • en Kaneshige, Riku
    • en Ohtsuka, Satomi
    • en Harada, Yuhei
    • en Kawamata, Issei
    • en Magari, Masaki
    • en Kanayama, Naoki
    • en Hatano, Naoya
    • en Sakagami, Hiroyuki
    • en Tokumitsu, Hiroshi
権利情報
  • © 2022 Federation of European Biochemical Societies.
主題
  • Other AMP-activated protein kinase
  • Other Arg/Pro-rich insert domain (RP-domain)
  • Other calcium/calmodulin-dependent protein kinase
  • Other calcium/calmodulin-dependent protein kinase kinase
  • Other substrate recognition
内容注記
  • Other Calcium/calmodulin-dependent protein kinase kinases (CaMKKs) activate CaMKI, CaMKIV, protein kinase B/Akt, and AMP-activated protein kinase (AMPK) by phosphorylating Thr residues in activation loops to mediate various Ca2+-signaling pathways. Mammalian cells expressing CaMKK alpha and CaMKK beta lacking Arg/Pro-rich insert domain (RP-domain) sequences showed impaired phosphorylation of AMPK alpha, CaMKI alpha, and CaMKIV, whereas the autophosphorylation activities of CaMKK mutants remained intact and were similar to those of wild-type CaMKKs. Liver kinase B1 (LKB1, an AMPK kinase) complexed with STRAD and MO25 and was unable to phosphorylate CaMKI alpha and CaMKIV; however, mutant LKB1 with the RP-domain sequences of CaMKK alpha and CaMKK beta inserted between kinase subdomains II and III acquired CaMKI alpha and CaMKIV phosphorylating activity in vitro and in transfected cultured cells. Furthermore, ionomycin-induced phosphorylation of hemagglutinin (HA)-CaMKI alpha at Thr177, HA-CaMKIV at Thr196, and HA-AMPK alpha at Thr172 in transfected cells was significantly suppressed by cotransfection of kinase-dead mutants of CaMKK isoforms, but these dominant-negative effects were abrogated with RP-deletion mutants, suggesting that sequestration of substrate kinases by loss-of-function CaMKK mutants requires the RP-domain. This was confirmed by pulldown experiments that showed that dominant-negative mutants of CaMKK alpha and CaMKK beta interact with target kinases but not RP-deletion mutants. Taken together, these results clearly indicate that both CaMKK isoforms require the RP-domain to recognize downstream kinases to interact with and phosphorylate Thr residues in their activation loops. Thus, the RP-domain may be a promising target for specific CaMKK inhibitors.
出版者 en Wiley
日付
    Issued2022-05-17
言語
  • eng
資源タイプ journal article
出版タイプ AM
資源識別子 URI https://ousar.lib.okayama-u.ac.jp/63525
関連
  • isIdenticalTo PMID 35490408
  • isIdenticalTo DOI https://doi.org/10.1111/febs.16467
収録誌情報
    • NCID AA11998513
    • ISSN 1742-464X
      • The FEBS Journal
      • 巻289 号19 開始ページ5971 終了ページ5984
ファイル
コンテンツ更新日時 2024-01-26