Premium
Modulation of Lemur Tyrosine Kinase 2 (LMTK2) Expression by TPA Response Elements
Author(s) -
Dey Isha A,
Bradbury Neil A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1005.4
Subject(s) - protein kinase c , tyrosine kinase , signal transduction , kinase , protein kinase a , chemistry , biology , microbiology and biotechnology , cancer research
Lemur Tyrosine Kinase 2 (LMTK2), a membrane anchored Serine/Threonine kinase, has been shown to be involved in a number of diseases, including cystic fibrosis and prostate cancer, as well as neuronal development and intracellular endocytic trafficking. Our previous studies have shown that LMTK2 is downregulated in prostate cancer, and that modulation of LMTK2 affects CFTR‐mediated chloride conductance at the plasma membrane of polarized epithelial cells. Moreover, CFTR, the Cl − selective anion channel mutated in cystic fibrosis has been found to a substrate for LMTK2 kinase activity. Based on these observations, we propose that LMTK2 to be a novel therapeutic target for both cystic fibrosis and prostate cancer. However, the precise mechanism to modulate the expression or activity of LMTK2 is not understood. In our current study, we have investigated the molecular mechanisms regulating LMTK2 gene expression. Since the promoter of a gene regulates its expression, we analyzed the region upstream of LMTK2 start codon for possible regulatory elements. We identified a putative TPA response element (TRE). TPA, a phorbol ester, is a synthetic activator of the classical and novel isoforms of Protein Kinase C, which in turn initiates a plethora of signaling cascades in a cell. We observed that TPA regulates LMTK2 expression in a dose‐ and time‐dependent manner, both at the protein and the mRNA levels. This effect is seen in multiple cell lines. However, TPA does not affect the stability of the LMTK2 mRNA transcript. Moreover, TPA increases the promoter activity of LMTK2. We further deduced that the TPA response on LMTK2 expression is mediated by direct binding of the activator Protein‐1 (AP‐1) complex on LMTK2 promoter. Overall, we have shown that LMTK2 is a TPA‐responsive element‐containing gene, and a novel gene upregulated downstream of PKC activation. Future studies will identify the cellular and extracellular signaling elements causing PKC activation and increased LMTK2 expression. Support or Funding Information R01HL102208 to NAB