PHLDA3 (Pleckstrin Homology-Like Domain, family A, member 3)

Note	NP_036528.1. Molecular weight: 13.9 kDa, 127 aa. https://www.ncbi.nlm.nih.gov/protein/NP_036528.1 - 23/Dec/18
	Figure 1 - Schematic representation of the PHLDA3 protein structure. The structure of the PHLDA3 protein is composed mainly of the pleckstrin like-domain (PHL).
Description	PHLDA3 is a 13.9kDa protein, composed of 127 amino mostly comprised of the PHL domain (120aa) (Frank et al., 1999). PHLDA3 PHL domain confers to this protein the ability of binding specifically to membrane lipids. According to in vitro binding assay, PHLDA3 protein binds to a wide combination of phosphatidylinositol phosphate (PIP): (PI(3)P, PI(4)P, PI(5)P, PI(3,4)P2, PI(4,5)P2, PI(3,5)P2 and PI(3,4,5)P3) (Kawase et al., 2009; Saxena et al., 2002). PHLDA3 has been reported as an AKT1 (Akt) pathway inhibitor and associated with tumor suppression (Kawase et al., 2009).
Expression	A RNA-seq performed in different tissue samples shown that PHLDA3 is broadly expressed in adrenal, appendix, brain, colon, duodenum, endometrium, esophagus, fat, gall bladder, heart, kidney, liver, lung, lymph node, ovary, pancreas, placenta, prostate, salivary gland, skin, small intestine, spleen, stomach, testis, thyroid and urinary bladder tissue (Fagerberg et al., 2014). PHLDA3 expression has been shown to be modulated by promoter methylation in prostate cancer and TP53 mutations in human infiltrating lobular breast cancer cells (Christgen et al., 2012; Mahapatra et al., 2012). Also, besides TP53 it was described that XBP1 transcription factor is implicated in PHLDA3 induction upon ER stress (Han et al., 2016). PHLDA3 was identified as a gene modulated by ochratoxin A (OTA) induced genotoxicity, it was upregulated in renal outer medulla cells after treatment with the renal carcinogen OTA in response to DNA damage. In other toxicogenomics studies, PHLDA3 was also proposed as a potential biomarker (Ellinger-Ziegelbauer et al., 2008; Furihata et al., 2018; Hibi et al., 2013; Uehara et al., 2008).
Localisation	PHLDA3 is primarly localized at the plasmatic membrane due its specificity binding to membrane phosphoinositides but can also be find in the cytoplasm and extracellular content.
	Figure 2 - Schematic diagram of the modulators and biological effects of PHDA3 expression. PHLDA3 is a p53-target gene activated in response to DNA damage and hypoxia. The gene can also be activated by Xbp1 in response to endoplasmic reticulum stress (ER stress). PHLDA3 induction leads to Akt pathway inhibition by binding to phosphoinositide competition leading to increased apoptosis and proliferation, and decreased cell reprograming efficiency.
Function	Murine PHLDA3 was first identified in 1999 and was designated Tih1 as the closest paralog of the imprinted gene Ipl (Frank et al., 1999). It was reported as a tumor suppressor gene. PHLDA3 protein function is still being studied, but it was reported as an AKT1 (Akt) pathway repressor by preventing Akt-binding to membrane lipids. Thus, PHLDA3 is a TP53 regulated repressor of Akt signaling by binding competition, so inhibits Akt activity via competitive binding to PIP3 (Kawase et al., 2009) and thereby acts as a dominant-negative form of Akt contributing to TP53-dependent apoptosis. It was reported that active TP53 localizes to the transcription start site of PHLDA3 and transcriptionally activates this gene. PHLDA3 was upregulated by hypoxia (Leszczynska et al., 2015), and there is a clear accumulation of TP53 at the response elements identified in PHLDA3, demonstrating direct transactivation of these genes in response to hypoxia in colorectal carcinoma, non-small-cell lung carcinoma, and nontumor lung fibroblast cells. It was observed after cisplatin treatment in testicular germ cell-derived human embryonal carcinoma cells that PHLDA3 and other genes downstream targets of TP53 are involved in response to DNA damage and events leading to cell death (Kerley-Hamilton et al., 2005). In renal tubular cells, cisplatin increases PHLDA3 in kidneys' tubules and in urinary content suggesting PHLDA3 protein as a kidney injury marker since it is urine-detectable (Lee et al., 2014; Lee, Kang, and Kim 2015). Furthermore, PHLDA3 exhibited statistically significant changes in gene expression in liver samples of rats treated with genotoxic hepatocarcinogens, suggesting that it may be a candidate marker gene for differentiating genotoxic hepatocarcinogens from non-genotoxic hepatocarcinogens (Suenaga et al., 2013). There is evidence that PHLDA3 is involved in zebrafish embryogenesis since PHLDA3 overexpression disrupted hemangioblast specification and affected intersegmental vessel development (ISV). It was suggested that overexpression of PHLDA3 inhibits ISV development by blocking the activation of AKT, it is supported by data showing a reversal of ISV defects induced by phlda3 overexpression upon Akt constitutively active form expression (Wang et al., 2018). In induced pluripotent stem cells (iPSC) PHLDA3 was expressed at a lower level and reduced gradually during the process of iPSCs generation; reprogramming efficiency was inhibited by PHLDA3 overexpression. Evidence supports that the mechanism by which PHLDA3 promotes decrease iPSC generation efficiency involves Akt- GSK3B activation during the reprogramming process (Qiao et al., 2017). Photoreceptor injury induced PHLDA3 expression in microglia, the resident macrophage in the CNS, data provide insights into the participation of PHLDA3 in the activation status of microglia under pathological conditions (Koso et al., 2016). PHLDA3 was the most significantly affected gene by thrombin knockout in zebrafish embryos but PHLDA3 function in embryonic development is still unclear (Day and Jagadeeswaran, 2009). The process of endomitosis consists of several rounds of DNA synthesis without division and leading to polyploidization in megakaryocytes. Downregulation of TP53-target genes in TP53 knock-down megakaryocytes supports the hypothesis that TP53 suppresses polyploidization during megakaryocytic differentiation by arresting DNA synthesis and inducing apoptosis. PHLDA3 together with other genes was identified as a gene through which TP53 mediates these biological effects in megakaryocytes (Apostolidis et al., 2012).
Homology	PHLDA3 gene is highly conserved in Euteleostomi and homologs have been found in P.troglodytes, M.mulatta, M.musculus, R.norvegicus, G.gallus and D.rerio.

For comments and suggestions or contributions, please contact us