Related Experiment Video

Updated: Aug 29, 2025

Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
08:37

Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog

Published on: November 5, 2014

10.0K

PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design

Jeetendra Kumar Nag1, Hodaya Malka1, Shoshana Sedley1

  • 1Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Molecular Cancer Therapeutics
|September 6, 2022
PubMed

Insights

Protease-activated receptor 4 (PAR4) drives colon cancer growth by interacting with PH-domain proteins. A novel peptide, Pc(4-4), inhibits PAR4 signaling and tumor development, offering a potential new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • G-protein-coupled receptors (GPCRs) are implicated in cancer, but their signaling pathways remain unclear.
  • Protease-activated receptors (PARs), a GPCR subgroup, are involved in epithelial cancers, with PAR4 acting as an oncogene.
  • PAR4's role in tumor generation and its specific molecular interactions require further investigation.

Purpose of the Study:

  • To identify and characterize the functional significance of a pleckstrin-homology (PH)-binding motif in PAR4.
  • To investigate the role of PAR4-PH protein interactions in colon cancer progression.
  • To evaluate the therapeutic potential of a novel peptide inhibitor, Pc(4-4), targeting PAR4 signaling.

Main Methods:

  • Identification of a PH-binding motif in PAR4 and analysis of its interaction with PH-containing proteins (Akt/PKB, Gab1, Sos1) using point mutations.
  • Selection and characterization of a cyclic peptide, Pc(4-4), targeting PAR2 and PAR4 PH-binding motifs.
  • Assessment of Pc(4-4)'s efficacy in inhibiting PAR4-mediated cellular invasion, migration, and tumor development in vivo, as well as EGFR phosphorylation.

Main Results:

  • A critical PH-binding motif was identified in PAR4's C-tail, essential for its association with proteins like Akt/PKB, Gab1, and Sos1.
  • The peptide Pc(4-4) effectively blocked PAR4-Akt/PKB interactions, suppressed PAR4-induced invasion and migration in vitro, and inhibited tumor growth in vivo.
  • Pc(4-4) also inhibited AYPGKF-induced EGFR phosphorylation, and PAR2/PAR4 were detected in aggressive cancer tissues.

Conclusions:

  • PAR4 utilizes a PH-binding motif for interactions crucial to colon cancer growth.
  • The peptide Pc(4-4) demonstrates significant potential as a therapeutic agent against PAR-expressing tumors and EGFR/erbB-expressing tumors, particularly in cases of therapeutic resistance.
  • Targeting PAR4-PH interactions represents a promising new strategy for cancer therapy development.

More Related Videos

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

8.7K
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.3K

Related Concept Videos

Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
2.7K
Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.3K
Protein-Drug Binding: Mechanism and Kinetics01:16

Protein-Drug Binding: Mechanism and Kinetics

Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
815
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
7.0K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
13.3K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.8K