A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression.
The cyclin-dependent kinase inhibitor, p27(Kip1), which regulates cell cycle progression, is controlled by its subcellular localization and subsequent degradation. p27(Kip1) is phosphorylated on serine 10 (S10) and threonine 187 (T187). Although the role of T187 and its phosphorylation by Cdks is well-known, the kinase that phosphorylates S10 and its effect on cell proliferation has not been defined. Here, we identify the kinase responsible for S10 phosphorylation as human kinase interacting stathmin (hKIS) and show that it regulates cell cycle progression. hKIS is a nuclear protein that binds the C-terminal domain of p27(Kip1) and phosphorylates it on S10 in vitro and in vivo, promoting its nuclear export to the cytoplasm. hKIS is activated by mitogens during G(0)/G(1), and expression of hKIS overcomes growth arrest induced by p27(Kip1). Depletion of KIS using small interfering RNA (siRNA) inhibits S10 phosphorylation and enhances growth arrest. p27(-/-) cells treated with KIS siRNA grow and progress to S/G(2 )similar to control treated cells, implicating p27(Kip1) as the critical target for KIS. Through phosphorylation of p27(Kip1) on S10, hKIS regulates cell cycle progression in response to mitogens.
Boehm
Manfred
M
Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA.
Yoshimoto
Takanobu
T
Crook
Martin F
MF
Nallamshetty
Shriram
S
True
Andrea
A
Nabel
Gary J
GJ
Nabel
Elizabeth G
EG
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000818:Animals; D001790:Blood Physiological Phenomena; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003593:Cytoplasm / Q000378:metabolism; D006133:Growth Substances / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering; D022661:RNA, Untranslated / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D010769:Phosphothreonine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; C530658:UHMK1 protein, human; C530659:Uhmk1 protein, mouse