title: c-Jun N-terminal kinase phosphorylation of MARCKSL1 determines actin stability and migration in neurons and in cancer cells.
abstract: 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-MARCKSL1(S120A,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.
authors: Turku Centre for Biotechnology, Åbo Akademi and University of Turku, BioCity, Turku, Finland.
authors: Benny
authors: B
authors: Björkblom
authors: Artur
authors: A
authors: Padzik
authors: Hasan
authors: H
authors: Mohammad
authors: Nina
authors: N
authors: Westerlund
authors: Emilia
authors: E
authors: Komulainen
authors: Patrik
authors: P
authors: Hollos
authors: Lotta
authors: L
authors: Parviainen
authors: Anastassios C
authors: AC
authors: Papageorgiou
authors: Kristiina
authors: K
authors: Iljin
authors: Olli
authors: O
authors: Kallioniemi
authors: Markku
authors: M
authors: Kallajoki
authors: Michael J
authors: MJ
authors: Courtney
authors: Mats
authors: M
authors: Mågård
authors: Peter
authors: P
authors: James
authors: Eleanor T
authors: ET
authors: Coffey
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002148:Calmodulin-Binding Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D002148:Calmodulin-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C070177:MARCKSL1 protein, human; C512945:Marcksl1 protein, mouse; C512942:Marcksl1 protein, rat; D008565:Membrane Proteins; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D048031:JNK Mitogen-Activated Protein Kinases