ZC3HC1, also known as NIPA (nuclear interacting partner of anaplastic lymphoma kinase), was identified as a protein partner of NPM-ALK fusion in two hybrid and co-imuunoprecipitation studies (Ouyang et al, 2003). ZC3HC1 is an F-box component of an SCF complex that targets nuclear CDKN1B (cyclin B1) for ubiquitination and degradation in interphase, regulating mitotic entry (Ouyang et al, 2003; Basserman et al, 2005; Illert et al, 2012). Binding to NPM-ALK depends on ALK kinase activity and is mediated through ZC3HC1 residues 306-402 (Ouyang et al, 2003). ZC3HC1 is predominantly a nuclear protein whose localization is governed by a nuclear localization signal (NLS). Although NPM is a nucleo-cytoplasmic protein, the fusion with ALK does not contain the endogenous NPM NLS, and the fusion is predominantly cytoplasmic. Nuclear localization of the fusion may be mediated by oligomerization with full-length NPM.
ZC3HC1 is phosphorylated downstream of NPM-ALK in a manner that depends on ERK2 (Ouyang et al, 2003; Basserman et al, 2005; Illert et al, 2012; Gegenbacher et al, 2019) Phosphorylation inactivates the SCF complex, allowing CDKN1B to accumulate and drive mitotic entry (Ouyang et al, 2003; Basserman et al, 2005; Illert et al, 2012).