Tyrosine Phosphorylation of the Pioneer Transcription Factor FoxA1 Promotes Activation of Estrogen Signaling

Abstract

The pioneer transcription factor FoxA1 plays an important role in estrogen signaling by opening closed chromatin and promoting recruitment of the estrogen receptor to its target regions in DNA. In this study, we analyzed tyrosine phosphorylation of FoxA1 by the non-receptor-type tyrosine kinase c-Abl. c-Abl was shown to phosphorylate FoxA1 at multiple sites, especially in the N- and C-terminal regions. Tyr429 and Tyr464 were identified as the major phosphorylation sites in the FoxA1 C-terminal region. The phosphomimetic and nonphosphorylatable FoxA1 mutants were generated by glutamic acid and phenylalanine substitutions at these tyrosine residues, respectively. The phosphomimetic FoxA1 promoted the activation of estrogen signaling, whereas the nonphosphorylatable FoxA1 suppressed its activation. Stimulation with the epidermal growth factor, which activates c-Abl, enhanced the activation of estrogen signaling. In contrast, the c-Abl inhibitor imatinib reduced its activation. The phosphomimetic FoxA1 mutant showed a higher affinity toward histone H3 than the wild-type. These results suggest that c-Abl-mediated phosphorylation of FoxA1 promotes the activation of estrogen signaling by inducing its binding to histones. J. Cell. Biochem. 118: 1453-1461, 2017. © 2016 Wiley Periodicals, Inc.

FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells

“…9) Tyrosine phosphorylation in the C-terminal region of FOXA1 was shown to enhance this chromatin remodeling activity. 10) Because estrogen receptor-α (ERα) depends on this chromatin remodeling activity, FOXA1 is crucial for the development of not only normal mammary gland but also estrogen-dependent breast cancer. 11,12) Recent studies have shown that FOXA1 suppresses EMT progression in pancreatic and prostate cancer.…”

Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530

“…The mechanism of Src-mediated suppression of apoptosis through Src substrates still remains poorly understood, possibly because protein-tyrosine phosphorylation is extremely unstable within cells. We, therefore, assume that phosphorylation levels of substrates are very rapidly regulated by a balance of the activities between tyrosine kinases and tyrosine phosphatases, like ON/OFF switching in a microprocessor (5,(22)(23)(24)(25)(26)(27)57). Nonetheless, carefully using a high dose of the potent tyrosine phosphatase inhibitor Na 3 VO 4 , we are able to detect tyrosine phosphorylation of endogenous proteins and have shown the significance of tyrosine-phosphorylated substrates (5,24,26,27).…”

“…We, therefore, assume that phosphorylation levels of substrates are very rapidly regulated by a balance of the activities between tyrosine kinases and tyrosine phosphatases, like ON/OFF switching in a microprocessor (5,(22)(23)(24)(25)(26)(27)57). Nonetheless, carefully using a high dose of the potent tyrosine phosphatase inhibitor Na 3 VO 4 , we are able to detect tyrosine phosphorylation of endogenous proteins and have shown the significance of tyrosine-phosphorylated substrates (5,24,26,27). Because we have learned from our own experiences that the inhibitory potency of Na 3 VO 4 , albeit an inorganic compound, against the activity of protein-tyrosine phosphatases is drastically lost (i) at neutral pH and (ii) by freeze-thawing, we dissolve Na 3 VO 4 in H 2 O just before use or store a Na 3 VO 4 stock solution in single-use aliquots at Ϫ20°C.…”

“…To explore in detail the roles of protein-tyrosine phosphorylation in cell functions, we recently performed phosphoproteomic analyses (5,25) and revealed novel roles for tyrosine phosphorylation of nuclear proteins, such as the heterochromatin protein KAP1 (KRAB-associated protein 1)/TIF1␤/TRIM28 (5), the transcription factors JunB (26) and FoxA1 (27), and the chromatinassociated protein AKAP8 (A-kinase anchoring protein 8) (24).…”

Invited Commentary: In a Genomic Era, Should We Promote Dopamine Homeostasis to Treat Opiate/ Opioid Abuse, Instead of Blocking Brain Dopamine Function?

“…An additional treatment example from this decade involves the use of "Imatinib"®, which is "a designer drug" used in the treatment of multiple cancers, most notably Philadelphia chromosomepositive (Ph+) chronic myelogenous leukemia. This drug has been designed, based upon insight into the disease's molecular pathology, with a certain degree of precision (Yamaguchi et al, 2016).…”