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The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis.
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- معلومة اضافية
- المصدر:
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
- بيانات النشر:
Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
- الموضوع:
- نبذة مختصرة :
The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.
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- Grant Information:
FRN53888 Canada Canadian Institutes of Health Research
- الرقم المعرف:
0 (CNNM3 protein, human)
0 (CNNM3 protein, mouse)
0 (Cation Transport Proteins)
0 (Cyclins)
0 (Immediate-Early Proteins)
EC 3.1.3.48 (Protein Tyrosine Phosphatases)
EC 3.1.3.48 (Ptp4a2 protein, mouse)
I38ZP9992A (Magnesium)
- الموضوع:
Date Created: 20140318 Date Completed: 20150428 Latest Revision: 20211021
- الموضوع:
20231215
- الرقم المعرف:
10.1038/onc.2014.33
- الرقم المعرف:
24632616
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