PHLDA1

What is PHLDA1 Protein?

PHLDA1, or pleckstrin homology-like domain family A member 1, is a protein encoded by the PHLDA1 gene in humans. This nuclear protein, characterized by its proline-histidine richness, is evolutionarily conserved. It plays a critical role in the anti-apoptotic effects attributable to insulin-like growth factor-1 (IGF-1). PHLDA1 has notable interactions with proteins such as RPL14, EIF3D, and PABPC4, which are crucial for various cellular processes. Understanding PHLDA1 is essential in fields like oncology and cell biology, where protein interactions and cellular survival mechanisms are crucial research areas.

What is the Function of PHLDA1 Protein?

PHLDA1 protein is integral to cellular survival mechanisms and apoptosis regulation. By modulating the anti-apoptotic effects of insulin-like growth factor 1 (IGF-1), PHLDA1 plays a crucial role in preventing programmed cell death, thereby supporting cell growth and maintenance. This protein is also pivotal in cellular signaling and the cell cycle's G2/M transition. Its interactions with various proteins underscore its importance in cancer biology, where disruptions in apoptosis are common. Understanding PHLDA1's function offers valuable insights into developing therapeutic strategies targeting cancer and other apoptosis-related diseases.

PHLDA1 Related Signaling Pathway

PHLDA1 is intricately involved in several signaling pathways crucial for maintaining cellular homeostasis and regulating apoptosis. Among these, the insulin-like growth factor 1 (IGF-1) pathway stands out, where PHLDA1 modulates anti-apoptotic signals that influence cell survival. This protein also plays a role in the Fas ligand (FasL) biosynthetic process and impacts the G2/M transition within the cell cycle. Through interactions with proteins like RPL14, EIF3D, and PABPC4, PHLDA1 affects various cellular processes, highlighting its potential as a therapeutic target in cancer treatment and other diseases characterized by disrupted signaling pathways.

PHLDA1 Related Diseases

PHLDA1 has been implicated in various diseases, primarily due to its role in apoptosis and cell proliferation. It is notably associated with cancer, where its dysregulation can contribute to tumor progression by inhibiting cell death and enhancing survival pathways. Besides cancer, PHLDA1 is linked to neurodegenerative disorders and cardiovascular diseases, as alterations in its expression can disrupt normal cellular functions. Understanding PHLDA1's involvement in these conditions is critical for developing targeted therapies that could mitigate its effects, offering new avenues for treating diseases characterized by abnormal cell growth and survival mechanisms.

Bioapplications of PHLDA1

The PHLDA1 protein offers promising bioapplications, particularly in cancer research and therapy. By understanding its role in modulating apoptosis and cell proliferation, scientists can develop targeted treatments aimed at regulating these processes in cancerous cells. In addition, PHLDA1's involvement in the insulin-like growth factor 1 (IGF-1) pathway presents opportunities for therapeutic interventions in metabolic and neurodegenerative disorders. Its function in the cell cycle and signaling pathways also makes it a valuable biomarker for disease progression. Overall, PHLDA1 holds significant potential for advancing medical research and developing innovative treatment strategies.

Case Study 1: Wang J. et al. Cell Mol Life Sci. 2022

Researchers discovered that PHLDA1, a protein interacting with Ras, acts as an oncogene in glioblastoma, promoting tumor growth and recurrence. They found PHLDA1 overexpressed in GBM tissues, driving cell proliferation through the Ras/Raf/Mek/Erk pathway. PHLDA1 competes with Src for binding to Ras, blocking Src's ability to phosphorylate Ras and keeping Ras active. This study provides new clues on glioma progression and suggests PHLDA1 as a potential target for GBM treatment.

• 
  Fig1. Endogenous PHLDA1 is predominantly expressed from short form of PHLDA1 in human glioblastoma cells.
• 
  Fig2. Recombined His-tagged Ras and HA-tagged PHLDA1 were incubated with active GST-tagged PHLDA1 following an in vitro kinase assay.

Case Study 2: Fearon AE. et al. Cell Rep. 2018

Researchers discovered that PHLDA1 downregulation is crucial for drug resistance in RTK-driven cancers. Using FGFR inhibitors in endometrial cancer cells, they identified an Akt-driven mechanism involving PHLDA1 reduction. This was also seen in breast and renal cancer patients treated with RTK inhibitors and in HER2+ breast cancer cells treated with trastuzumab. Knocking down PHLDA1 alone made cells resistant to RTK inhibitors, while restoring PHLDA1 expression re-sensitized them to therapy. This highlights PHLDA1 as a biomarker for drug response and a potential target to overcome resistance.

• 
  Fig3. Western blot showing downregulation of PHLDA1 levels in parental MFE-296 cells.
• 
  Fig4. Western blot showing PHLDA1 levels in parental and resistant HCC1954 cells following treatment with doxycycline.

• 
  Fig1. Model for PHLDA1 and Src competing for binding with Ras. (Jiutao Wang, 2022)
• 
  Fig2. Model for PHLDA1 Silencing as a Mechanism of Acquired Drug Resistance In normal growth conditions. (Abbie E Fearon, 2018)

PHLDA1 has several biochemical functions, for example, protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PHLDA1 itself. We selected most functions PHLDA1 had, and list some proteins which have the same functions with PHLDA1. You can find most of the proteins on our site.

Function	Related Protein
protein binding	GSG2,CNOT6L,LSM2,CSRNP2,EIF4G1,HLX,PPP1R16A,TBX5A,RIT1,TTR

PHLDA1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PHLDA1 here. Most of them are supplied by our site. Hope this information will be useful for your research of PHLDA1.

MDFI;EIF3D;RPL14;PABPC4;PLSCR1;melB1;KRTAP4-12;EGFR;ERBB3