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New findings about a temperature sensor in the skin could lead to novel approaches to controlling excess hair growth and treating skin cancers.

The common denominator that unites these seemingly unrelated processes is a versatile protein called TRPV3. The new research shows that in addition to serving as a temperature sensor, the protein is important for proper hair growth and skin health. The work, by University of Michigan cell biologist Haoxing Xu and colleagues, is described in a paper published in the April 16 issue of the journal Cell.

Found mainly in cells called keratinocytes in the outer layer of skin, TRPV3 functions as a calcium channel---a gateway that, when activated, allows calcium to pass through and deliver signals that stimulate processes such as muscle contraction, release of hormones or firing of neurons.

Some years ago, Xu identified TRPV3 and found that it is activated by warm temperatures and certain spices such as oregano. "Those are its sensory functions, but I wanted to know if it also plays a role in the basic biology of keratinocytes," said Xu. To get at that question, Xu's team created "knockout" mice, which lacked TRPV3.

The TRPV3-deficient mice had peculiar, wavy hair, and the outermost layer of their skin, which normally forms a barrier against germs and poisonous substances, was thinner than it should be. This was interesting, because the same two abnormalities, wavy hair and a thin epidermal barrier, are known to occur in mice with particular mutations. One such mutation affects a growth factor called TGF-alpha; the other affects a cell-surface receptor called EGFR, which is activated by TGF-alpha. Conversely, when TGF-alpha and EGFR are overactive, hairlessness and skin disorders, including skin cancer, may result.

The fact that the loss of TRPV3 produced the same effects as abnormalities in TGF-alpha and EGFR made Xu and colleagues curious about relationships among the three proteins. Their experiments revealed a chain of steps in which activation of TRPV3 leads to release of TGF-alpha, which activates EGFR. Activation of EGFR then feeds back to increase TRPV3 channel activity, forming a positive signaling loop.

Finding that the three proteins all work in concert is important, given the roles that TGF-alpha and EGFR play in skin diseases and abnormal hair growth, said Xu. "Many current anti-cancer drugs target EGFR, and our identification of TRPV3 as an essential regulator of EGFR places TRPV3 as a new drug target for cancer and other skin disorders. The additional connection to hair growth could also make TRPV3 useful in controlling that process."

 

Xu's coauthors on the Cell paper are Xiping Cheng, Lily Hu, Dongbiao Shen, Xian-ping Dong, Mohammad Samie, Jayne Knoff, Brian Eisinger and Mei-ling Liu at U-M; Jie Jin and David Clapham of Children's Hospital Boston; Susan Huang and Michael Caterina of Johns Hopkins University School of Medicine; Peter Dempsey, Lowell Evan Michael and Andrzej Dlugosz of the U-M School of Medicine; and Nancy Andrews of Duke University School of Medicine.

The research was supported by Howard Hughes Medical Institute, the University of Michigan and the National Institutes of Health.

More information:

Haoxing Xu: http://www.mcdb.lsa.umich.edu/faculty_haoxingx.html
Cell: http://www.cell.com/