Myotubularins mutation in CMT

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Mol Cell Biol. 2005 May;25(9):3630-8.

The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin-

Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca2+-

Activated K+ Channel KCa3.1.

Srivastava S, Li Z, Lin L, Liu G, Ko K, Coetzee WA, Skolnik EY.

Skirball Institute, New York University Medical Center, 540 First

Ave., New York, NY 10016.

Myotubularins (MTMs) belong to a large subfamily of phosphatases that

dephosphorylate the 3' position of phosphatidylinositol 3-phosphate

[PI(3)P] and PI(3,5)P(2). MTM1 is mutated in X-linked myotubular

myopathy, and MTMR2 and MTMR13 are mutated in Charcot-Marie-Tooth

syndrome.

However, little is known about the general mechanism(s) whereby MTMs

are regulated or the specific biological processes regulated by the

different MTMs. We identified a Ca(2+)-activated K channel, K(Ca)3.1

(also known as KCa4, IKCa1, hIK1, or SK4), that specifically

interacts with the MTMR6 subfamily of MTMs via coiled coil (CC)

domains on both proteins. Overexpression of MTMR6 inhibited K(Ca)3.1

channel activity, and this inhibition required MTMR6's CC and

phosphatase domains.

This inhibition is specific; MTM1, a closely related MTM, did not

inhibit K(Ca)3.1. However, a chimeric MTM1 in which the MTM1 CC

domain was swapped for the MTMR6 CC domain inhibited K(Ca)3.1,

indicating that MTM CC domains are sufficient to confer target

specificity. K(Ca)3.1 was also inhibited by the PI(3) kinase

inhibitors LY294002 and wortmannin, and this inhibition was rescued

by the addition of PI(3)P, but not other phosphoinositides, to the

patch pipette solution. PI(3)P also rescued the inhibition of K(Ca)

3.1 by MTMR6 overexpression.

These data, when taken together, indicate that K(Ca)3.1 is regulated

by PI(3)P and that MTMR6 inhibits K(Ca)3.1 by dephosphorylating the

3' position of PI(3)P, possibly leading to decreased PI(3)P in lipid

microdomains adjacent to K(Ca)3.1. K(Ca)3.1 plays important roles in

controlling proliferation by T cells, vascular smooth muscle cells,

and some cancer cell lines.

Thus, our findings not only provide unique insights into the

regulation of K(Ca)3.1 channel activity but also raise the

possibility that MTMs play important roles in the negative regulation

of T cells and in conditions associated with pathological cell

proliferation, such as cancer and atherosclerosis.