The membrane-associated form of cyclin D1 enhances cellular invasion

Ke Chen,Richard G Pestell,Jun Zhao,Zhiping Li,Agnese Di Rocco,Hallgeir Rui,Timothy G Pestell,Yunguang Sun,Michael P Lisanti,Duanwen Shen,Mathew C Casimiro,Samuel Achilefu,Xuanmao Jiao,Peter A Mccue,Anthony Ashton

doi:10.1038/s41389-020-00266-y

Abstract

The essential G1-cyclin, CCND1, is a collaborative nuclear oncogene that is frequently overexpressed in cancer. D-type cyclins bind and activate CDK4 and CDK6 thereby contributing to G1–S cell-cycle progression. In addition to the nucleus, herein cyclin D1 was also located in the cytoplasmic membrane. In contrast with the nuclear-localized form of cyclin D1 (cyclin D1NL), the cytoplasmic membrane-localized form of cyclin D1 (cyclin D1MEM) induced transwell migration and the velocity of cellular migration. The cyclin D1MEM was sufficient to induce G1–S cell-cycle progression, cellular proliferation, and colony formation. The cyclin D1MEM was sufficient to induce phosphorylation of the serine threonine kinase Akt (Ser473) and augmented extranuclear localized 17β-estradiol dendrimer conjugate (EDC)-mediated phosphorylation of Akt (Ser473). These studies suggest distinct subcellular compartments of cell cycle proteins may convey distinct functions.

Highlights

Introduction The cyclinD1 (CCND1) gene, encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein, in order to promote cell cycle progression[1,2,3]
Cyclin D1 is located at the cytoplasmic membrane The endogenous cytoplasmic membrane-associated protein PACSIN II was shown to bind cyclin D1 in liver tissue[23] and cyclin D1 bound to PACSIN II and paxillin (Pxn) in 3T3 cells[21,23]
PACSIN II and tyrosine phosphorylated paxillin colocated at the leading edge Fig. 1c, Fig. S2B), consistent with prior studies conducted of the individual proteins in other cell types[21,23,24]

Summary

Introduction

Introduction The cyclinD1 (CCND1) gene, encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein (pRB), in order to promote cell cycle progression[1,2,3]. Synthesized cyclin D1 associates with CDK4/6 to form the holoenzyme that phosphorylates pRB, releasing E2F family transcription factors and inducing a gene expression network contributing to G1/S entry. Studies demonstrated that cyclin D1 functions as a nuclear collaborative oncogene[4]. In this regard a cyclin D1 cDNA clone contributed to cellular transformation by complementing a transformation defective adenovirus E1A oncogene[4]. Cyclin D1 is actively synthesized and located exclusively in an extranuclear location in hibernating hematopoietic stem cells (HSC)[16], in postmitotic neurons[17], cardiomyocytes[18], and hepatocytes[19]. Cyclin D1 has been identified in the cytoplasmic membrane[20,21,22] and shown to bind and regulate the function of several cytoplasmic membrane-associated proteins including PACSIN II (Protein kinase C and Casein kinase Substrate In Neurons protein 2)[23] known as syndapin), Filamin A24 and paxillin[21]

Methods

Results

Conclusion