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| | Scheme of the PDZK1IP1/MAP17 protein. Blue barrs indicate transmembrane regions. Pink barr indicates PDZ-binding domain. |
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| Description | MAP17 is a small, non-glycosylated membrane-associated protein of 17 kDa, which is located on the plasma membrane and the Golgi apparatus. The protein sequence possesses a hydrophobic amino-terminus containing 13 amino acids that encodes a PDZ-binding domain and two transmembrane regions. MAP17 binds several PDZ domain-containing proteins, including PDZK1, NHERF proteins, NaPiIIa and NHe3. Together with NHRF3 and NHRF4, overexpression of MAP17 in opossum kidney cells leads to internalization of NaPilla to the trans-Golgi network. In normal tissue MAP17 is only expressed in the proximal tubules of kidney cells. The physiological role of MAP17 in proximal tubules is not known, but it stimulates specific Na-dependent transport of mannose and glucose in Xenopus oocytes and some mammary cells. |
| Expression | MAP17 protein is overexpressed in a great variety of human carcinomas. Immunohistochemical analysis of MAP17 during cancer progression shows, at least in prostate and ovarian carcinomas, that overexpression of the protein strongly correlates with tumoral progression (P<0.0001). Many tumor cells also express MAP17 protein. |
| Localisation | Apical end of proximal tubule cells in kidney. |
| Function | MAP17 binds several PDZ domain-containing proteins, including PDZK1, NHERF proteins, NaPiIIa and NHe3. Overexpression of MAP17 into opossum kidney cells participates, together with NHRF3 and NHRF4 in NaPiIIa internalization to the transgolgi network. The physiological role of MAP17 in proximal tubules is not known but it stimulates specific Na-dependent transport of mannose and glucose in Xenopus oocytes and in mammary cells. |
| Homology | Higly conserved protein troughout the evolution. |
| Entity | Cancer |
| Disease | Carcinomas of different origin, melanoma, etc. |
| Prognosis | Expression levels increase with stage in most carcinomas. |
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| Overexpression of MAP17 in colon carcinoma. |
| Oncogenesis | MAP17 (PDZK1IP1, DD96) enhances tumorigenic properties of melanoma cells through ROS increase (Guijarro et al., 2007b). Tumor cells that overexpress MAP17 show an increased tumoral phenotype with enhanced proliferative capabilities both in presence or absence of contact inhibition, decreased apoptotic sensitivity and increased migration. MAP17-expressing clones also grow better in nude mice. The increased malignant cell behavior induced by MAP17 are associated with an increase in ROS production, and the treatment of MAP17-expressing cells with antioxidants results in a reduction in the tumorigenic properties of these cells. Treatment of melanoma cells with inhibitors of Na+-coupled co-transporters lead to an inhibition of ROS increase and a decrease in the malignant cell behavior in MAP17-expressing clones. Finally, we show that MAP17-dependent ROS increase and tumorigenesis are dependent on its PDZ-binding domain, since disruption of its sequence by point mutations abolish its ability to enhance ROS production and tumorigenesis.
At the molecular level MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through ROS-mediated activation of the PI3K/AKT signalling pathway (Guijarro et al., 2007d). A fraction of PTEN undergoes oxidation in MAP17-overexpressing cells. Furthermore, activation of AKT by MAP17 as measured by Thr308 phosphorylation was independent of PI3K activity. Importantly, modulation of ROS by antioxidant treatment prevented activation of AKT, restoring the level of apoptosis in serum starved Rat1/c-Myc fibroblasts (Guijarro et al., 2007d).
MAP17 is overexpressed in a great variety of human carcinomas (Guijarro et al., 2007c). Immunohistochemical analysis of MAP17 during cancer progression shows in prostatic and ovarian carcinomas that overexpression of the protein strongly correlates with tumoral progression (Guijarro et al., 2007c). |
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| Entity | Skin diseases |
| Disease | Abnormal keratinocyte differentiation.
In the meta-analysis of public microarray databases for different skin diseases, Noh and cols (Noh et al., 2010) revealed that MAP17 is commonly up-regulated suggesting that may be potentially associated with the abnormal keratinocyte differentiation. MAP17 was significantly up-regulated in response to interferon-gamma, interleukin 4 (IL-4), IL-6, IL-17A or IL-22 in normal human epidermal keratinocytes (NHEK). Interestingly, the PDZK1 gene is localized within the atopic dermatitis-linked region on human chromosome 1q21. In an attempt to evaluate whether MAP17 regulates the expression of cornified envelope-associated genes at the 1q21 locus, such as filaggrin, loricrin and involucrin, these authors found that the over-expression of MAP17 in HaCaT keratinocytes significantly decreased the expression of filaggrin, a cornified envelope-associated gene. Taken together, the Th cell cytokine-induced up-regulation of MAP17 expression may be linked to the down-regulation of filaggrin, which may be associated with the abnormal epidermal differentiation observed in the dermatological diseases (Noh et al., 2010). |
| Prognosis | . |
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| Identification of a novel gene, selectively up-regulated in human carcinomas, using the differential display technique. |
| Kocher O, Cheresh P, Brown LF, Lee SW. |
| Clin Cancer Res. 1995 Oct;1(10):1209-15. |
| PMID 9815914 |
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| Identification and partial characterization of a novel membrane-associated protein (MAP17) up-regulated in human carcinomas and modulating cell replication and tumor growth. |
| Kocher O, Cheresh P, Lee SW. |
| Am J Pathol. 1996 Aug;149(2):493-500. |
| PMID 8701988 |
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| The membrane-associated protein pKe#192/MAP17 in human keratinocytes. |
| Jaeger C, Schaefer BM, Wallich R, Kramer MD. |
| J Invest Dermatol. 2000 Sep;115(3):375-80. |
| PMID 10951271 |
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| Rat kidney MAP17 induces cotransport of Na-mannose and Na-glucose in Xenopus laevis oocytes. |
| Blasco T, Aramayona JJ, Alcalde AI, Catalan J, Sarasa M, Sorribas V. |
| Am J Physiol Renal Physiol. 2003 Oct;285(4):F799-810. Epub 2003 Jun 17. |
| PMID 12812916 |
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| Interactions of MAP17 with the NaPi-IIa/PDZK1 protein complex in renal proximal tubular cells. |
| Pribanic S, Gisler SM, Bacic D, Madjdpour C, Hernando N, Sorribas V, Gantenbein A, Biber J, Murer H. |
| Am J Physiol Renal Physiol. 2003 Oct;285(4):F784-91. Epub 2003 Jul 1. |
| PMID 12837682 |
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| Large scale genetic screen identifies MAP17 as protein bypassing TNF-induced growth arrest. |
| Guijarro MV, Castro ME, Romero L, Moneo V, Carnero A. |
| J Cell Biochem. 2007a May 1;101(1):112-21. |
| PMID 17230460 |
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| MAP17 enhances the malignant behavior of tumor cells through ROS increase. |
| Guijarro MV, Leal JF, Blanco-Aparicio C, Alonso S, Fominaya J, Lleonart M, Castellvi J, Ramon y Cajal S, Carnero A. |
| Carcinogenesis. 2007b Oct;28(10):2096-104. Epub 2007 Jun 4. |
| PMID 17548903 |
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| MAP17 overexpression is a common characteristic of carcinomas. |
| Guijarro MV, Leal JF, Fominaya J, Blanco-Aparicio C, Alonso S, Lleonart M, Castellvi J, Ruiz L, Ramon Y Cajal S, Carnero A. |
| Carcinogenesis. 2007c Aug;28(8):1646-52. Epub 2007 Apr 9. |
| PMID 17426052 |
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| MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation. |
| Guijarro MV, Link W, Rosado A, Leal JF, Carnero A. |
| Carcinogenesis. 2007d Dec;28(12):2443-50. Epub 2007 Aug 3. |
| PMID 17675338 |
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| Interaction of MAP17 with NHERF3/4 induces translocation of the renal Na/Pi IIa transporter to the trans-Golgi. |
| Lanaspa MA, Giral H, Breusegem SY, Halaihel N, Baile G, Catalan J, Carrodeguas JA, Barry NP, Levi M, Sorribas V. |
| Am J Physiol Renal Physiol. 2007 Jan;292(1):F230-42. Epub 2006 Aug 22. |
| PMID 16926447 |
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| MAP17 is associated with the T-helper cell cytokine-induced down-regulation of filaggrin transcription in human keratinocytes. |
| Noh M, Yeo H, Ko J, Kim HK, Lee CH. |
| Exp Dermatol. 2010 Apr;19(4):355-62. Epub 2009 Jul 8. |
| PMID 19601982 |
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