A growth factor-dependent nuclear kinase phosphorylates p27Kip1 and regulates cell cycle progression

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Abstract
The cyclin‐dependent kinase inhibitor, p27Kip1, which regulates cell cycle progression, is controlled by its subcellular localization and subsequent degradation. p27Kip1 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 p27Kip1 and phosphorylates it on S10 in vitro and in vivo , promoting its nuclear export to the cytoplasm. hKIS is activated by mitogens during G/G1, and expression of hKIS overcomes growth arrest induced by p27Kip1. 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/G2similar to control treated cells, implicating p27Kip1 as the critical target for KIS. Through phosphorylation of p27Kip1 on S10, hKIS regulates cell cycle progression in response to mitogens.