L-3-phosphoserine phosphatase (L3PSP) is a widely expressed member of the haloacid dehalogenase (HAD) superfamily and its enzyme activity is the irreversible and rate limiting step in L-serine biosynthesis. Dysregulation of L-serine biosynthesis is featured in neurological disorders, Williams-Beuren syndrome, skin ichthyosis and a variety of epithelial neoplasms. However, the significance of altered L3PSP activity on the initiation and course of these diseases is still not clear. We recently identified L3PSP by microarray analysis to be altered in an integrin transgenic mouse model that is predisposed to epidermal hyperplasia and skin inflammation indicating that L3PSP may be a critical regulator of epidermal homeostasis. The goal of this proposal is to define the role for L3PSP in skin development and epidermal disease. Our preliminary results show that ectopic expression of L3PSP in the proliferative layer of the epidermis leads to defects in hair follicle morphogenesis, decreased hair follicle number and dysregulated hair follicle cycling. We have also uncovered novel L3PSP interaction candidate proteins that function in sumoylation pathways and proteins that mediate Fas ligand apoptosis. We will determine if the effects of L3PSP expression in disrupted hair follicle growth and cycling are dependent on its phosphatase activity and if L3PSP expression stimulates epidermal keratinocytes to undergo apoptosis. To demonstrate a new role(s) for L3PSP outside of L-serine biosynthesis we will conduct biochemical studies to validate putative interactions between L3PSP and candidate proteins identified by yeast two-hybrid analysis. Finally, to determine the requirement for L3PSP in epidermal homeostasis we will generate murine and human skin that is deficient in L3PSP expression and measure the effect on epidermal proliferation, apoptosis and hair follicle morphogenesis. Lay summary: Overall we plan to ascertain whether a protein normally thought to function in basic cellular amino acid metabolism may also regulate the growth and maintenance of hair follicles by stimulating programmed cell death pathways in skin cells. In doing so, the studies outlined in this proposal will have important implications for hair follicle biology and epithelial cell survival in general. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR054071-02
Application #
7257074
Study Section
Special Emphasis Panel (ZAR1-EHB-J (M1))
Program Officer
Baker, Carl
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$78,166
Indirect Cost
Name
Columbia University (N.Y.)
Department
Dermatology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Bachelor, Michael A; Lu, Yan; Owens, David M (2011) L-3-Phosphoserine phosphatase (PSPH) regulates cutaneous squamous cell carcinoma proliferation independent of L-serine biosynthesis. J Dermatol Sci 63:164-72
Yan, Xiaohong; Owens, David M (2008) The skin: a home to multiple classes of epithelial progenitor cells. Stem Cell Rev 4:113-8