HEI10 negatively regulates cell invasion by inhibiting cyclin B/Cdk1 and other promotility proteins

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Oncogene (Impact Factor: 8.46). 08/2007; 26(33):4825-32. DOI: 10.1038/sj.onc.1210282
Source: PubMed


Human enhancer of invasion, clone 10 (HEI10) (CCNB1IP1) was first described as a RING-finger family ubiquitin ligase that regulates cell cycle by interacting with cyclin B and promoting its degradation. Subsequently, other studies suggested specific upregulation of HEI10 in metastatic melanoma and demonstrated direct interaction between HEI10 and the tumor suppressor Merlin, encoded by the neurofibromatosis 2 gene. These and other results led us to hypothesize that HEI10 also influences the processes of cell migration and metastasis. We here show that cells with depleted HEI10 both migrate more rapidly and invade more effectively than control cells. HEI10 depletion post-transcriptionally increases the expression of a group of promotility regulatory proteins including p130Cas, paxillin, Cdk1 and cyclin B2, but excluding Merlin. Among these, only inhibition of Cdk1/cyclin B activity specifically reversed the motility and invasion of HEI10-depleted cells. Finally, HEI10 is abundantly transcribed in many human tissues, and particularly abundant in some tumor cell lines, suggesting that it may be commonly involved in coordinating cell cycle with cell migration and invasion.

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Available from: Erica A Golemis, Oct 07, 2015
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    • "In addition to cNCC migration related factors, many cell cycle related genes are differentially expressed in Wnt1-Cre Hand2 CKOs (Holler et al., 2010). The most highly regulated of these genes (up 37 fold) was cyclin B1 interacting protein 1 (Ccnb1ip1), which is an ubiquitin ligase that promotes the degradation of cyclin B. While the details of its function during development remain unclear, recent malignancy related research suggests that Ccnb1ip1 plays a role in coordinating the cell cycle with cell migration and invasion (Singh et al., 2007)—functions required for OFT septation and valve formation . Others included cdk6, a serine/threonine kinase that regulates the G0 to G1 transition by phosphorylating retinoblastoma protein (pRb) (Malumbres and Barbacid, 2005), Insm1, a regulator of NCC derived sympathetic neuron development which also interacts with cyclin D1 in the heart (Liu et al., 2006; Pellegrino et al., 2011), and several histones. "
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    Differentiation 04/2012; 84(1):79-88. DOI:10.1016/j.diff.2012.03.002 · 3.44 Impact Factor
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    • "Ccnb1ip1 encodes a coiled-coil RING domain-containing protein, whereas Ccnb1ip1mei4 bears a donor splice site mutation resulting in an aberrantly spliced transcript [3]. Studies of CCNB1IP1 in cultured somatic cells implicated a role for this putative ubiquitin E3 ligase in Cyclin B regulation, cell cycle progression, and cell invasion [5,6]. However, the exact function of CCNB1IP1 in meiotic recombination remains is unclear. "
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    ABSTRACT: The RING domain-containing protein CCNB1IP1 (Cyclin B1 Interacting Protein 1) is a putative ubiquitin E3 ligase that is essential for chiasmata formation, and hence fertility, in mice. Previous studies in cultured cells indicated that CCNB1IP1 targets Cyclin B for degradation, thus playing a role in cell cycle regulation. Mice homozygous for a mutant allele (mei4) of Ccnb1ip1 display no detectable phenotype other than meiotic failure from an absence of chiasmata. CCNB1IP1 is not conserved in key model organisms such as yeast and Drosophila, and there are no features of the protein that implicate clear mechanisms for a role in recombination. To gain insight into CCNB1IP1's function in meiotic cells, we raised a specific antibody and determined that the protein appears in pachynema. This indicates that CCNB1IP1 is involved with crossover intermediate maturation, rather than early (leptotene) specification of a subset of SPO11-induced double strand breaks towards the crossover pathway. Additionally, a yeast 2-hybrid (Y2H) screen revealed that CCNB1IP1 interacts with SUMO2 and a set of proteins enriched for consensus sumoylation sites. The Y2H studies, combined with scrutiny of CCNB1IP1 domains, implicate this protein as an E3 ligase of the sumoylation cascade. We hypothesize CCNB1IP1 represents a novel meiosis-specific SUMO E3 ligase critical to resolution of recombination intermediates into mature chiasmata.
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    ABSTRACT: The neurofibromatosis 2 (NF2) tumor suppressor protein merlin is commonly mutated in human benign brain tumors. The gene altered in NF2 was located on human chromosome 22q12 in 1993 and the encoded protein named merlin and schwannomin. Merlin has homology to ERM family proteins, ezrin, radixin, and moesin, within the protein 4.1 superfamily. In efforts to determine merlin function several groups have discovered 34 merlin interacting proteins, including ezrin, radixin, moesin, CD44, layilin, paxillin, actin, N-WASP, betaII-spectrin, microtubules, TRBP, eIF3c, PIKE, NHERF, MAP, RalGDS, RhoGDI, EG1/magicin, HEI10, HRS, syntenin, caspr/paranodin, DCC, NGB, CRM1/exportin, SCHIP1, MYPT-1-PP1delta, RIbeta, PKA, PAK (three types), calpain and Drosophila expanded. Many of the proteins that interact with the merlin N-terminal domain also bind ezrin, while other merlin interacting proteins do not bind other members of the ERM family. Merlin also interacts with itself. This review describes these proteins, their possible roles in NF2, and the resultant hypothesized merlin functions. Review of all of the merlin interacting proteins and functional consequences of losses of these interactions reveals multiple merlin actions in PI3-kinase, MAP kinase and small GTPase signaling pathways that might be targeted to inhibit the proliferation of NF2 tumors.
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