Epidermal hyperproliferation in mice lacking fatty acid transport protein 4 (FATP4) involves ectopic EGF receptor and STAT3 signaling.
Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective epidermal barrier; they die neonatally due to dehydration and restricted movements. Both the skin phenotype and the lethality are rescued by transgene-driven expression of FATP4 solely in suprabasal keratinocytes. Here we show that Fatp4 mutants exhibit epidermal hyperplasia resulting from an increased number of proliferating suprabasal cells. In addition, barrier formation initiates precociously but never progresses to completion. To investigate possible mechanisms whereby Fatp4 influences skin development, we identified misregulated genes in Fatp4 mutants. Remarkably, three members of the epidermal growth factor (EGF) family (Ereg, Areg, and Epgn) showed increased expression that was associated with elevated epidermal activation of the EGF receptor (EGFR) and STAT3, a downstream effector of EGFR signaling. Both Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, and curcumin, an inhibitor of both STAT3 and EGFR, attenuated STAT3 activation/nuclear translocation, reduced skin thickening, and partially suppressed the barrier abnormalities. These data identify FATP4 activity as negatively influencing EGFR activation and the resulting STAT3 signaling during normal skin development. These findings have important implications for understanding the pathogenesis of ichthyosis prematurity syndrome, a disease recently shown to be caused by FATP4 mutations.
Lin
Meei-Hua
MH
Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Chang
Kuo-Wei
KW
Lin
Shu-Chun
SC
Miner
Jeffrey H
JH
D000818:Animals; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D066260:Epiregulin; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050612:Fatty Acid Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation / Q000187:drug effects; D010641:Phenotype; D011799:Quinazolines; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000378:metabolism; D012871:Skin Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020032:Tyrphostins
D066260:Epiregulin; C587881:Ereg protein, mouse; D050612:Fatty Acid Transport Proteins; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors