title: PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b.
abstract: Cyclin D1 overexpression is a common feature of many human malignancies. Genomic deletion analysis has demonstrated a key role for cyclin D1 in cellular proliferation, angiogenesis, and cellular migration. To investigate the mechanisms contributing to cyclin D1 functions, we purified cyclin D1a-associated complexes by affinity chromatography and identified the PACSIN 2 (protein kinase C and casein kinase substrate in neurons 2) protein by mass spectrometry. The PACSIN 2, but not the related PACSIN 1 and 3, directly bound wild-type cyclin D1 (cyclin D1a) at the carboxyl terminus, and failed to bind cyclin D1b, the alternative splicing variant of cyclin D1. PACSIN 2 knockdown induced cellular migration and reduced cell spreading in LNCaP cells expressing cyclin D1a. In cyclin D1(-/-) mouse embryonic fibroblasts (MEFs), cyclin D1a, but not cyclin D1b, reduced the cell spreading to a polarized morphology. siPACSIN 2 had no effect on cellular migration of cyclin D1(-/-) MEFs. Cyclin D1a restored the migratory ability of cyclin D1(-/-) MEFs, which was further enhanced by knocking down PACSIN 2 with siRNA. The cyclin D1-associated protein, PACSIN 2, regulates cell spreading and migration, which are dependent on cyclin D1 expression.
authors.affiliation: Department of Cancer Biology, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Li
authors.forename: Markus
authors.initials: M
authors.lastname: Plomann
authors.forename: Zhishun
authors.initials: Z
authors.lastname: Xu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530104:CCND1 protein, human; C120714:PACSIN2 protein, human; D020033:Protein Isoforms; D022821:RNA Splice Sites; D019938:Cyclin D1