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c-Jun N-Terminal Kinase Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells

Författare:
  • Benny Bjorkblom
  • Artur Padzik
  • Hasan Mohammad
  • Nina Westerlund
  • Emilia Komulainen
  • Patrik Hollos
  • Lotta Parviainen
  • Anastassios C. Papageorgiou
  • Kristiina Iljin
  • Olli Kallioniemi
  • Markku Kallajoki
  • Michael J. Courtney
  • Mats Mågård
  • Peter James
  • Eleanor T. Coffey
Publiceringsår: 2012
Språk: Engelska
Sidor: 3513-3526
Publikation/Tidskrift/Serie: Molecular and Cellular Biology
Volym: 32
Nummer: 17
Dokumenttyp: Artikel
Förlag: American Society for Microbiology

Sammanfattning

Cell migration is a fundamental biological function, critical during development and regeneration, whereas deregulated migration underlies neurological birth defects and cancer metastasis. MARCKS-like protein 1 (MARCKSL1) is widely expressed in nervous tissue, where, like Jun N-terminal protein kinase (JNK), it is required for neural tube formation, though the mechanism is unknown. Here we show that MARCKSL1 is directly phosphorylated by JNK on C-terminal residues (S120, T148, and T183). This phosphorylation enables MARCKSL1 to bundle and stabilize F-actin, increase filopodium numbers and dynamics, and retard migration in neurons. Conversely, when MARCKSL1 phosphorylation is inhibited, actin mobility increases and filopodium formation is compromised whereas lamellipodium formation is enhanced, as is cell migration. We find that MARCKSL1 mRNA is upregulated in a broad range of cancer types and that MARCKSL1 protein is strongly induced in primary prostate carcinomas. Gene knockdown in prostate cancer cells or in neurons reveals a critical role for MARCKSL1 in migration that is dependent on the phosphorylation state; phosphomimetic MARCKSL1 (MARCKSL1(S120D,T148D,T183D)) inhibits whereas dephospho-MARCKSL(1S120A,T148A,T183A) induces migration. In summary, these data show that JNK phosphorylation of MARCKSL1 regulates actin homeostasis, filopodium and lamellipodium formation, and neuronal migration under physiological conditions and that, when ectopically expressed in prostate cancer cells, MARCKSL1 again determines cell movement.

Disputation

Nyckelord

  • Technology and Engineering
  • Medicine and Health Sciences

Övrigt

Published
Yes
  • ISSN: 0270-7306

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