Biology:RMDN3
 Generic protein structure example |
Regulator of microtubule dynamics protein 3 (RMDN3), more commonly known as Protein tyrosine phosphatase interacting protein 51 (PTPIP51), is a protein that in humans is encoded by the RMDN3 gene on chromosome 15.[1][2] This protein contributes to multiple biological functions, including cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis, and has been associated with numerous cancers.[3][4][5]
Structure
PTPIP51 contains two conserved domains, called conserved region 1 (CR1) and conserved region 2 (CR2), which serve as binding sites for 14-3-3 proteins. Close to these conserved domains are two tyrosine residues, tyrosine 53 and 158, which serve as phosphorylation sites for various kinases.[4] In addition, PTPIP51 has a mitochondrial targeting sequence at its N-terminal which is responsible for inducing apoptosis, though some splicing variants lack this sequence.[1][6] It also contains a 33-residue coiled coil domain at positions 92 – 124.[1] Crystal structure of TPR domain of PTPIP51 was determined.[7]
Function
PTPIP51 is a member of the RMDN protein family and localizes to the outer mitochondrial membrane, cytoplasm, and nucleus.[1] This protein is involved in cellular differentiation, proliferation, motility, cytoskeleton formation, and apoptosis.[3][4] These biological functions thus serve to facilitate mammalian development through processes such as placental villi formation and angiogenesis.[3][6] In particular, it is expressed in differentiated cells and tissues, such as follicular and inter-follicular epidermis, epithelia, skeletal muscle, testis, and nervous tissue.[3][6] PTPIP51 is also expressed differentially in neutrophils, but not other immune cells, and thus may partake in immune cell signaling and myeloid development by interacting with TCPTP and PTP1B.[6] Its interactions with PTP1B, along with the proteins 14-3-3β, Raf-1, c-Src, PKA, and DAGKα, determine the mechanisms by which it influences the mitogen-activated protein kinase (MAPK) pathway.[4] PTPIP51 has been observed to induce apoptosis by disrupting the mitochondrial membrane potential, resulting in the release of cytochrome c.[8] In vitro phospholipid binding and transfer functions has been reported [7]
Clinical significance
There is currently little known about the RMDN3 protein with respect to its clinical significance other than an apparent role in oncology. The main mechanism for the RMDN3 protein is its role as an apoptotic constituent. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[9] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
Both the protein and mRNA of PTPIP51 have been implicated in various carcinomas, including prostate carcinoma (PCa), keratinocyte carcinoma, basal cell carcinomas, and squamous cell carcinomas.[3][5][6] It is hypothesized that overexpression of PTPIP51 in PCa results from retrotransposon elements activated by CpG island hypomethylation, which has been observed in late prostate carcinogenesis.[3] Moreover, the protein has been observed to interact with PTP1B to influence the MAPK pathway in acute myeloid leukemia.[4] In addition to cancers, PTPIP51 has been associated with benign prostate hyperplasia (BPH) and, by extension, with BPH-related conditions, including aging and lower urinary tract dysfunction.[3]
Interactions
RMDN3 has been shown to interact with:
- PTP1B,[3][4]
- TCPTP,[3][4]
- c-Src,[3][4]
- 14-3-3β,[4]
- 14-3-3γ,[4]
- Raf-1,[4]
- PKA,[4]
- DAGKα,[4] and
- VAPB.[10]
References
- ↑ 1.0 1.1 1.2 1.3 "Q96TC7 - RMD3_HUMAN". https://www.uniprot.org/uniprot/Q96TC7.
- ↑ "Entrez Gene: Regulator of microtubule dynamics protein 3". https://www.ncbi.nlm.nih.gov/gene/55177.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 "PTPIP51 mRNA and protein expression in tissue microarrays and promoter methylation of benign prostate hyperplasia and prostate carcinoma". The Prostate 69 (16): 1751–62. Dec 2009. doi:10.1002/pros.21025. PMID 19691131.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 "PTPIP51 in protein interactions: regulation and in situ interacting partners". Cell Biochemistry and Biophysics 63 (3): 211–22. Jul 2012. doi:10.1007/s12013-012-9357-y. PMID 22544307.
- ↑ 5.0 5.1 "Differentiation-dependent PTPIP51 expression in human skeletal muscle cell culture". The Journal of Histochemistry and Cytochemistry 57 (5): 425–35. May 2009. doi:10.1369/jhc.2008.952846. PMID 19124842.
- ↑ 6.0 6.1 6.2 6.3 6.4 "The novel protein PTPIP51 is expressed in human keratinocyte carcinomas and their surrounding stroma". Journal of Cellular and Molecular Medicine 12 (5B): 2083–95. Oct 2008. doi:10.1111/j.1582-4934.2008.00198.x. PMID 19012732.
- ↑ 7.0 7.1 "Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes.". EMBO Reports 22 (6): e51323. Jun 2021. doi:10.15252/embr.202051323. PMID 33938112.
- ↑ "Protein tyrosine phosphatase interacting protein 51 (PTPIP51) is a novel mitochondria protein with an N-terminal mitochondrial targeting sequence and induces apoptosis". Apoptosis 11 (9): 1489–501. Sep 2006. doi:10.1007/s10495-006-8882-9. PMID 16820967.
- ↑ "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer 26 (4): 239–57. Aug 1972. doi:10.1038/bjc.1972.33. PMID 4561027.
- ↑ De Vos, KJ; Mórotz, GM; Stoica, R; Tudor, EL; Lau, KF; Ackerley, S; Warley, A; Shaw, CE et al. (15 March 2012). "VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis.". Human Molecular Genetics 21 (6): 1299–311. doi:10.1093/hmg/ddr559. PMID 22131369.
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