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<Structure load='MYO_PDZ_BD.pdb' size='400' frame='true' align='right' caption='Prediction of the PDZ binding domain of Myopodin . Lambert et al. ESyPred3D:Prediction of Proteins 3D structures. Bioinformatics 2002)' scene='Insert optional scene name here' />
===Synaptopodin-2===


==MYOPODIN==
==Introduction==
Myopodin protein, encoded by the gene SYNPO2[http://www.uniprot.org/uniprot/Q9UMS6], also called genethonin-2, synaptopodin-2, synaptopodin-like and fesselin, was first described in 2001 by Weins ''et al.'', is widely expressed in striated- and smooth-muscle cells <ref> PMID:11673475 </ref> <ref> PMID:12869577 </ref>. At least six isoforms result from alternative splicing. Their size varies between 76 kDa and 136 kDa and they show differential tissue distribution. The cause of this size difference remains to be established, but appears to be due to post-translational modifications <ref> PMID:20554076 </ref> <ref> PMID:18371299 </ref> <ref> PMID:11696420</ref> <ref> PMID:12917631 </ref> <ref> PMID:18588515 </ref>.  
The protein synaptopodin-2 (encoded by the gene SYNPO2[http://www.uniprot.org/uniprot/Q9UMS6]), also called '''myopodin''', genethonin-2, synaptopodin-like and fesselin, is together with synaptopodin and tritopodin/CHAP a member of the podin protein family. It is widely expressed in striated, heart and smooth muscle cells where it localizes to Z-disks and dense bodies, respectively <ref name="r1"> PMID:11673475 </ref>. Myopodin is a multiadapter protein that interacts with filamentous actin, α-actinin and filamin. Different isoforms result from alternative splicing and alternative promoter usage and the predicted size of the resulting proteins varies between 74 kDa and 136 kDa; these variants show differential tissue distribution. The discrepancy between calculated molecular mass and apparent mobility in SDS-PAGE is at present still unclear, but might be due to post-translational modifications <ref> PMID:20554076 </ref> <ref> PMID:18371299 </ref> <ref> PMID:11696420</ref> <ref> PMID:12917631 </ref> <ref> PMID:18588515 </ref>. The lower molecular mass myopodin isoforms are dual compartment proteins that redistribute between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced manner <ref> PMID:C2150840 </ref>. Although its biological function is still undefined, recent findings support a role for myopodin as a z-disc multiadaptor protein (96).
 
==Sequence Annotation==
Myopodin contains one PPXY motif and multiple PXXP motifs <ref name="r1"> PMID:11673475 </ref>. Beside 2 lysine-rich NLS sites (consensus motif K-K/RX-K/R) myopodin provides 2 binding sites for 14-3-3(consensus motif a: RSXpS/TXP; b: RXXXpS/TXP Biophys Rev (2010) 2:181-189). These sites seem to be indispensable for effective shuttling of myopodin from the Z-disk into the nucleus <ref> PMCID:PMC2171942 </ref>. Phosphorylation of myopodin within the 14-3-3 binding sites (S225 and T272) by protein kinase A and Ca<sup>2+</sup>/calmodulin-dependent protein kinase II abrogates the binding with α -actinin and promotes the binding with 14-3-3 and importin α <ref> PMID:17923693 </ref>. Another important domain present in myopodin is the PDZ domain (postsynaptic density 95, discs large, and zonula occludens-1). PDZ domains are protein-protein interaction modules that can mediate multiple biological processes such as vesicle transport, ion channel signaling, and signal transduction in several tissues. PDZ domains in myopodin are of unknown function <ref> PMID:18371299 </ref>.


== Function==
Myopodin is a dual compartment protein that displays actin-bundling activity and redistributes between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced fashion <ref> PMID:11673475 </ref>.
In undifferentiated myoblasts, myopodin is expressed preferentially in the nucleus and only weakly in the cytoplasm, whereas in differentiated myotubes, Myopodin is incorporated into the Z-disc with no detectable nuclear expression and this expression pattern suggests that myopodin may be involved in the regulation of myocyte differentiation <ref> PMID:11673475 </ref>.
Myopodin has also been identified as a tumor suppressor gene that is frequently deleted in aggressive prostate cancer <ref> PMID:15111326 </ref>. Expression of myopodin protein suppresses both tumor growth and metastasis in vitro and in vivo <ref> PMID:15111326 </ref>.


[[Image:Myopodin.jpg|800px]]


[[Image:Myopodin.jpg|500x]]


==Function==
Myopodin is a dual compartment protein that redistributes between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced fashion, and in addition displays actin-bundling activity <ref name="r1"> PMID:11673475 </ref>.
In undifferentiated myoblasts, myopodin seems to be expressed preferentially in the nucleus and only weakly in the cytoplasm, whereas in differentiating myotubes, myopodin is incorporated into the Z-disc with no detectable nuclear expression, suggesting that myopodin may be involved in the regulation of myocyte differentiation <ref name="r1"> PMID:11673475 </ref> <ref> PMID:19360353 </ref>.
Myopodin has also been identified as a tumor suppressor gene that is frequently deleted in aggressive prostate cancer <ref> PMID:15111326 </ref>. Expression of myopodin protein suppresses both tumor growth and metastasis in vitro and in vivo <ref> PMID:15111326 </ref>.


== Myopodin Interactions ==
== Myopodin Interactions ==


Actin was the first binding partner of Myopodin to be identified <ref> PMID:9314539 </ref>. Myopodin has a novel actin binding site <ref> PMID:11673475 </ref> that was identified by producing truncated fragments from Myopodin and the smallest fragment that bound to F-actin contained residues 410–563 of mouse Myopodin. Actin has an essential role in anchoring Myopodin into the Z-disc <ref> PMID:11673475 </ref> <ref> PMID:17923693 </ref>.
Actin was the first binding partner of myopodin to be identified. Actin binding was narrowed down to residues 410–563 of murine myopodin <ref name="r1"> PMID:11673475 </ref>.
Myopodin binds to α-actinin and this interaction has been shown to involve the Spectrin  filament domain repeat region of α-actinin <ref> PMID:16450054 </ref>. It's believed that synaptopodin family members are involved in the organization and anchoring of actin in the cell and might be necessary for the correct localization of α-actinin. This hypothesis is supported by recent findings where myopodin expression precedes actin and α-actinin expression <ref> PMID:20554076 </ref>.
Myopodin also binds to α-actinin via its spectrin repeats <ref> PMID:16450054 </ref>, <ref> PMID:20554076 </ref> . Myopodin may be generally involved in the organization and anchoring of actin in muscle cells and might be required for the correct localization of α-actinin. This hypothesis is supported by recent findings where myopodin expression precedes actin and α-actinin expression <ref> PMID:20554076 </ref>.
A newly identified filamin-binding region within the molecule was reported by performing yeast two-hybrid assays using carboxy-terminally and/or amino-terminally truncated constructs <ref> PMID:20554076 </ref>. The interaction was mapped to a fragment encompassing amino acids 240–521 of Myopodin, i.e. a region that contains two of the previously described homology regions shared by myopodin and synaptopodin <ref> PMID:11696420 </ref>. The alternative transcription offers the possibility of expression of two isoforms of Myopodin, which probably differ in their binding properties for these PDZ binding domain detected, however, there is preliminary evidence that the PDZ binding domain from Myopodin interacts with the C terminal part of Synemin <ref> PMID:16631741 </ref>.  
A filamin-binding region was mapped to a fragment encompassing amino acids 240–521 of myopodin, i.e. a region that contains two of the previously described homology regions shared by myopodin and synaptopodin <ref> PMID:20554076 </ref>.
Through yeast two-hybrid analysis, was found the interaction between Myopodin and Zyxin both in vitro and in vivo and that this interaction leads to slower migration of prostate cancer cells and reduced invasiveness <ref> PMID:16885336 </ref>.
Yeast two-hybrid analysis also identified an interaction  of myopodin with zyxin, which leads to slower migration of prostate cancer cells and reduced invasiveness <ref> PMID:16885336 </ref>.
In cardiomyocytes, Myopodin forms a Z-disc signaling complex with α-Actinin, Calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), Muscle-specific A-kinase anchoring protein, and Myomegalin. Calcineurin keeps Myopodin dephosphorylated preventing 14-3-3ß binding to myopodin. Upon activation of PKA/CaMKII or inhibition of Calcineurin, Myopodin undergoes phosphorylation, enabling its interaction with 14-3-3ß, which releases Myopodin from the Z-disc-anchoring proteins and induces its nuclear import. This novel intracellular signaling pathway suggests that changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart <ref> PMID:17923693 </ref>.
In cardiomyocytes, myopodin forms a Z-disc signaling complex with α-actinin, calcineurin, Ca<sup>2+</sup>/calmodulin-dependent kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Calcineurin keeps myopodin dephosphorylated preventing 14-3-3ß binding to myopodin. Upon activation of PKA/CaMKII or inhibition of calcineurin, myopodin undergoes phosphorylation, enabling its interaction with 14-3-3ß, which releases myopodin from the Z-disc-anchoring proteins and induces its nuclear import. This novel intracellular signaling pathway suggests that changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart <ref> PMID:17923693 </ref>.


[[Image:Myopodin interaction with FLNC.jpg|700px]]
[[Image:Myopodin interaction with Filamin C.jpg|700px]]
[[Image:Model for the regulation of myopodin's subcellular localization in cardiac myocytes.jpg|500px]]
[[Image:Model for the regulation of Myopodin's subcellular localization in Cardiomyocytes.jpg|700px]]


==Pathology==
==Pathology==
Already in 2001 Lin et al showed that ''SYNPO2'' gene exhibit frequently delations in aggresive prostata cancer <ref> PMID:11696420</ref>. Later analysis gave the evidence that Myopodin plays an important role as tumor suppressor, considering that in normal urothelium of the bladder Myopodin is localized in the cytoplasm and in the nucleus, however in mutated tissue of superficial and invasive bladder tumor is observed a reduced nuclear expression of Myopodin <ref> PMID:12917631 </ref>. Furthermore the expression of Myopodin suppressed tumor growth and metastasis <ref> PMID:15111326 </ref>. However these observations appear in contradiction with other experiments, where the expression of Myopodin at the protein level could be verify merely in muscle cells <ref> PMID:15111326 </ref> <ref> PMID:15111326 </ref>.
The SYNPO2 gene frequently exhibits deletions in aggresive prostate cancer tissues and statistical analysis indicates that deletion of myopodin is highly correlated with the invasiveness of prostate cancers, and thus may hold promise as an important prognostic marker for prostate cancers <ref> PMID:11696420</ref>. Myopodin was suggested to play a role as tumor suppressor, because in normal urothelium of the bladder myopodin is localized both in the cytoplasm and in the nucleus, wheras in superficial and invasive bladder tumors, reduced nuclear expression of myopodin was observed <ref> PMID:12917631 </ref>. The expression of myopodin suppressed tumor growth and metastasis <ref> PMID:15111326 </ref>.  
 


==References==
==References==
<references/>
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[[Category: Z-disk]]
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