Phosphatase Subfamily PTPRK

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPRK

PTPRG is a receptor PTP family involved in metazoan neural development and maybe cancer.

Evolution

PTPRK subfamily is vertebrate specific. There are four copies in human, which have similar genomic organization, despite great disparities in gene size due to variations in intron length [1].

Domain Structure

PTPRK subfamily has dual intracellular catalytic domains. All human members of PTPRK subfamily has the same extracellular domain combination: a MAM domain, 1 Ig domain and 4 FN3 domain [2, 3, 4].

MAM domain is essential for homophilic cell-cell interaction and helps determine the specificity of these interactions. Truncated PTPRM is properly expressed at the cell surface but fails to promote cell-cell adhesion. Homophilic cell adhesion is fully restored in a chimeric PTPRM molecule containing the MAM domain of PTPRK. However, this chimeric RPTP mu does not interact with either PTPRK or PTPRM [2].

Ig domain (of PTPRM) contains the homophilic binding site and regulates subcellular localization [5].

Functions

PTPRK subfamily mediates homophilic cell-cell interaction [2, 6, 7, 8, 9]. They are putative tumor suppressors in various types of cancer. They also function in nervous system.

PTPRK (LAR)

PTPRK is a putative tumor suppressor [10] in various types of cancer, such as breast cancer [11], prostate cancer [12], lymphoma [13] and glioma [14]. It plays its function as tumor suppressor through different mechanisms. PTPRK influences transactivating activity of beta-catenin in non-tumoral and neoplastic cells by regulating the balance between signaling and adhesive beta-catenin which is a molecule endowed with a dual function being involved both in cell adhesion and in Wnt signaling pathway [15]. PTPRK is a key factor in coordinating apoptosis via the regulation of MAPK pathways, in particular the JNK pathway in prostate cancer cells [12]. PTPRK dephosphorylates Epidermal growth factor receptor (EGFR) and thereby regulates EGFR tyrosine phosphorylation and subsequent promotes human keratinocyte survival and proliferation [16]. It is worthy pointing out that PTPRK is the target of transforming growth factor {beta} (TGF-{beta})-Smad, which inhibits proliferation and promotes cell migration [13, 17, 18]. PTPRK also dephosphorylates Src [18].

PTPRK regulates CD4+ T cell development through ERK1/2-mediated signaling [19].

PTPRM

PTPRM mediates homophilic cell-cell adhesion [2, 8, 20, 21]. It associates with and dephosphorylates cadherin and catenin [22, 23, 24].

PTPRM functions in developing nervous system. The catalytic activity and adhesion mediated by PTPRM regulate lamination of the retina [25, 26, 27].

PTPRM is also expressed in specific vascular endothelial beds [28, 29].

PTPRM binds and recruits the scaffolding protein RACK1, a scaffolding protein, to cell-cell contacts [30, 31].

PTPRT (RPTPrho)

PTPRT is restrictively expressed in the central nervous system and functions in regulating cadherin-mediated cell adhesion cellular adhesion in the central nervous system [9, 32, 33]. In brain, PTPRT regulates synapse formation through interaction with cell adhesion molecules, and this function and the phosphatase activity are attenuated through tyrosine phosphorylation by the synaptic tyrosine kinase Fyn [34].

PTPRT is a putative tumor suppressor in colon cancer. PTPRT specifically dephosphorylated signal transducer and activator of transcription 3 (STAT3) at Y705 is essential for the function of STAT3 (Note: PTPRD dephosphorylate STAT3 Y705, as well). Overexpression of normal PTPRT in colorectal cancer cells reduced the expression of STAT3 target genes [35]. PTPRT knockout mice exhibit increased levels of colonic paxillin phosphorylation at residue Y88, which is found as a common feature of human colon cancers [36].

PTPRT is the most frequently mutated PTP in different types of human cancers and is believed to be a tumor suppressor in colon cancer [37] and head and neck squamous cell carcinoma [38], but it does not play a critical role in the development of common human cancers [39]. It is worthy pointing out that more than half of the identified tumor-derived mutations are located in the extracellular part, particularly MAM domain and Ig domain, which mediates the homophilic interaction of cell-cell adhesion [40].

PTPRU (PTP-RO/hPTP-J/PTP pi/PTP lambda)

PTPRU is predominately found in adult brain, lung, and kidney [41, 42]. PTPRU is glycosylated and expressed at the cell surface. PTPRU localizes to the adherens junctions with cell adhesion molecules like catenin and E-cadherin [7]. PTPRU directly binds and dephosphorylates beta-catenin, which is a key molecule involved in both cell adhesion and Wnt signaling pathway [43, 44]. PTPRU-deficient mice associated with hypertension and low glomerular filtration rate [45].

PTPRU was weakly detected in the peripheral blood lymphocytes, thymus, and spleen even though gene expression was relatively high in the Jurkat T lymphoma cell line. Moreover, PTPRU gene expression was down-regulated after Jurkat cells (an immortalized line of human T lymphocyte cells) were stimulated by either Phorbol myristate acetage (PMA) or calcium ionophore [46, 47].

References

Error fetching PMID 16973135:
Error fetching PMID 10094839:
Error fetching PMID 7961788:
Error fetching PMID 8394372:
Error fetching PMID 7642713:
Error fetching PMID 9531566:
Error fetching PMID 11278757:
Error fetching PMID 11801604:
Error fetching PMID 14623235:
Error fetching PMID 15080886:
Error fetching PMID 1655529:
Error fetching PMID 8393854:
Error fetching PMID 17223850:
Error fetching PMID 19816407:
Error fetching PMID 24395800:
Error fetching PMID 9602027:
Error fetching PMID 9486824:
Error fetching PMID 21517784:
Error fetching PMID 15491993:
Error fetching PMID 18644975:
Error fetching PMID 17360477:
Error fetching PMID 20133777:
Error fetching PMID 10753936:
Error fetching PMID 15040814:
Error fetching PMID 8264577:
Error fetching PMID 7782276:
Error fetching PMID 8700514:
Error fetching PMID 8870675:
Error fetching PMID 9722959:
Error fetching PMID 16263724:
Error fetching PMID 24002526:
Error fetching PMID 23552869:
Error fetching PMID 23696788:
Error fetching PMID 17720884:
Error fetching PMID 21094132:
Error fetching PMID 16263724:
Error fetching PMID 15899872:
Error fetching PMID 8941358:
Error fetching PMID 19800317:
Error fetching PMID 9070223:
Error fetching PMID 9054423:
Error fetching PMID 8989520:
Error fetching PMID 12501215:
Error fetching PMID 16574648: