spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online March 19, 2008
doi: 10.1242/10.1242/jcs.022038

Journal of Cell Science 121, 925-932 (2008)
Published by The Company of Biologists 2008
This Article
Right arrow Summary Freely available
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Maxwell, C. A.
Right arrow Articles by Turley, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maxwell, C. A.
Right arrow Articles by Turley, E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions?

Christopher Alan Maxwell1,*, James McCarthy2 and Eva Turley3,*

1 Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain
2 University of Minnesota, Department of Laboratory Medicine and Pathology, Minnesota Comprehensive Cancer Center, Minneapolis, MN, USA
3 London Regional Cancer Program, London Health Sciences, Department of Oncology/Biochemistry, University of Western Ontario, London ON N6A 4L6, Canada


Figure 1
View larger version (59K):
[in this window]
[in a new window]

  		Fig. 1. Routes for non-conventional protein export. (A) Transporter channels. Cytoplasmic proteins can be exported through transporter-protein channels and then captured by cell-surface counter receptors. As an example, FGF2 is shown being exported through the ABC transporter and then captured by a heparin sulphate proteoglycan. (B) Protein-release complex. Other cytoplasmic proteins, such as epimorphin (or FGF1, not shown), associate with a protein-release complex that is composed of S100A13 and synaptotagmin 1 that then binds to annexin 2. The epimorphin protein-release complex is localized to, and flipped through, the cytoplasmic membrane in response to Ca2+ and phosphatidylserine. Released epimorphin then binds to {alpha}v-integrin, resulting in activation of morphogenic signaling cascades. (C) Flippase activity. An alternate route of export results from cytoplasmic proteins binding to transporter proteins that have intrinsic flippase activity when stimulated by phosphatidylserine. (D,E) Exocytosis and membrane blebbing. Additional mechanisms of non-conventional export include exocytosis (D) and membrane blebbing (E). Cytoplasmic and/or nuclear proteins such as Ku are released by exocytosis of exosomes, but cytoplasmic proteins can also be exported in vesicles formed by membrane blebbing.

 

Figure 2
View larger version (72K):
[in this window]
[in a new window]

  		Fig. 2. Extracellular and intracellular functions of RHAMM. (A) Cell-surface RHAMM promotes the activation of signaling cascades. Shown is one molecular mechanism for this. Cell-surface RHAMM, which is not an integral membrane protein, partners with CD44 and, in the presence of hyaluronan, activates ERK1/2 [indicated as phosphorylated (PO4) ERK1,2], which results in the expression of genes that are required for motility and invasion. (B) In X. laevis egg extracts, a RAN-GTP gradient, which is established by chromosome-bound guanine nucleotide-exchange factor RCC1 activity, is required for anastral mitotic-spindle assembly. RAN-GTP activity regulates the function of a number of mitotic-spindle proteins, including importins, that then form inhibitory complexes with both spindle-assembly factors and TPX2. For example, by binding importins (indicated as step 1), RAN-GTP releases TPX2 (step 2), which is a major activator of Aurora kinase A (AURKA). TPX2 directly activates AURKA by protecting an autophosphorylated residue (step 3). AURKA, in turn, can phosphorylate (PO4) BRCA1 to facilitate G2-M transition (step 4). Via an interaction with the dynein complex, RHAMM localizes to the spindle pole, at which it interacts with {gamma}-tubulin (step 5). RHAMM also interacts with TPX2 and dynein, thereby having the potential to localize TPX2 to spindle poles (step 5). The BRCA1-BARD1 complex modifies TPX2 localization and spindle assembly by attenuating RHAMM function through ubiquitylation (Ub) (step 6). Ubiquitylation of RHAMM, and subsequently its degradation, probably releases TPX2 from the spindle pole (step 7), thus affecting AURKA activation and G2-M progression.

 

Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



© The Company of Biologists Ltd 2008