Breast Cancer Regulation by Stathmin1

Stathmin-1 (Stmn1), also referred to as oncoprotein-18 (Op18), is an evolutionarily well conserved 17 kDa cytoplasmic phosphoprotein that is highly expressed in a wide variety of cancers; its abundance seems to be necessary for the maintenance of transformed phenotypes. Breast cancers exhibit high levels of Stmn1, which plays a regulatory role in microtubule dynamics. One of the key properties of microtubules is that of 'dynamic instability' which comprises the continuous switching between catastrophes (depolymerization or shrinkage phase) and rescues (polymerization or growing phase) of individual microtubules. Stmn1 regulates microtubule dynamics by promoting depolymerization of microtubules and/or preventing polymerization of tubulin heterodimers. Upon entry into mitosis, microtubules polymerize to form the mitotic spindle, a cellular structure that is essential for accurate chromosome segregation and cell division. The microtubule-depolymerizing activity of Stmn1 is switched off at the onset of mitosis by phosphorylation to allow microtubule polymerization and assembly of the mitotic spindle. Phosphorylated Stmn1 has to be reactivated by dephosphorylation before cells exit mitosis and enter a new interphase.Stmn1 is phosphorylated on up to four sites (Ser16, Ser25, Ser38 and Ser63) in response to regulatory signals within cells in order to maintain equilibrium during microtubule polymerization. Various protein kinases that are known to phosphorylate Stmn1 include CamKs, MAPKs, CDKs, PKA, PRKX and KIS (kinase interacting stathmin). Upstream factors that activate these kinases include hormones and neurotransmitters acting through GPCRs. G-protein signaling couples Rac and Cdc42 activation with RhoA activation, to phosphorylate and inactivate Stmn1. Rac and Cdc42 relay signals to PAK1 and cyclins that in turn inhibit anti-microtubule action of Stmn1 through phosphorylation. RhoA acting independently of ROCK, also modulates the cell cycle by regulating expression of p21(CIP1) and p27(KIP1) and this reflects on Stmn1 phosphorylation and tubulin dynamics. Dephosphorylation of Stmn1 by an okadaic acid sensitive PP1 and PP2A is crucial for the ability of cells to exit mitosis. A similar effect is also shown by taxanes, group of chemotherapy drugs that includes taxol and taxotere, specifically used to kill cancer cells of mammary gland by stopping their growth.Stmn1 promotes microtubule-destabilization by promoting microtubule depolymerization or by a tubulin sequestering activity that inhibits microtubule polymerization. Both activities are regulated by phosphorylation, which inactivates Stmn1, prevents its binding to tubulin and interferes with the sensitivity of breast cancer cells to anti-microtubule drugs.