Hyaluronan Mediated Motility Receptor (HMMR) Encodes an Evolutionarily Conserved Homeostasis, Mitosis, and Meiosis Regulator Rather than a Hyaluronan Receptor.

Zhengcheng He,Christopher A Maxwell,Marisa Connell,Lin Mei

doi:10.3390/cells9040819

Abstract

Hyaluronan is an extracellular matrix component that absorbs water in tissues and engages cell surface receptors, like Cluster of Differentiation 44 (CD44), to promote cellular growth and movement. Consequently, CD44 demarks stem cells in normal tissues and tumor-initiating cells isolated from neoplastic tissues. Hyaluronan mediated motility receptor (HMMR, also known as RHAMM) is another one of few defined hyaluronan receptors. HMMR is also associated with neoplastic processes and its role in cancer progression is often attributed to hyaluronan-mediated signaling. But, HMMR is an intracellular, microtubule-associated, spindle assembly factor that localizes protein complexes to augment the activities of mitotic kinases, like polo-like kinase 1 and Aurora kinase A, and control dynein and kinesin motor activities. Expression of HMMR is elevated in cells prior to and during mitosis and tissues with detectable HMMR expression tend to be highly proliferative, including neoplastic tissues. Moreover, HMMR is a breast cancer susceptibility gene product. Here, we briefly review the associations between HMMR and tumorigenesis as well as the structure and evolution of HMMR, which identifies Hmmr-like gene products in several insect species that do not produce hyaluronan. This review supports the designation of HMMR as a homeostasis, mitosis, and meiosis regulator, and clarifies how its dysfunction may promote the tumorigenic process and cancer progression.

Highlights

Hyaluronan is an extracellular matrix component that absorbs water in tissues
For Hyaluronan Mediated Motility Receptor (HMMR), the basic leucine zipper (bZip) motif locates the protein to the centrosome and HMMR complexes with a significant fraction of targeting protein for Xklp2 (TPX2) in a cell cycle-dependent manner [31,32,33,34]
Using this tool [56], HMMR is found to be co-expressed with TOP2A, KIF11, TPX2, ECT2, BUB1, KIF20A, NUSAP1, KIF20B, SMC2, and CCNA2; each of these gene products are involved with cell cycle regulation, spindle organization, and chromosome segregation

Summary

Introduction

Hyaluronan is an extracellular matrix component that absorbs water in tissues. Due to its hydrating nature, hyaluronan has many commercial uses, including cosmetic applications, but it regulates the proliferation of certain stem cell populations and may enable certain hallmarks of cancer [1,2]. In 1999, five additional exons were cloned at the N-terminus of HMMR; as the gene product was found to be exclusively intracellular, it was suggested that it be renamed Intracellular hyaluronan binding protein (IHABP) [8,9]. This complicated history and the confusing nomenclature (i.e., RHAMM1, RHAMM1v4, RHAMM2, or IHABP) serves to cloud our understanding of the gene product’s function both as a microtubule-associated spindle assembly factor and as a putative hyaluronan receptor. An unbiased examination of the evolution of the HMMR gene and the gene product’s structure may provide clarity to the physiological functions and how those functions are perverted during the tumorigenic process

The Conserved Basic C-Terminal Domain in HMMR Is a Leucine Zipper Motif

Structural Domains in HMMR

Evolution of HMMR

HMMR localizes

Findings

Conclusions