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Published on: July 17, 2020
Protein tyrosine phosphatase PTPH1 potentiates receptor tyrosine kinase HER2 oncogenesis via a PDZ-coupled and
Xiaomei Qi1, Fang Wang1,2, Linda Thomas1
1Department of Pharmacology and Toxicology, Medical College of Wisconsin Milwaukee, Wisconsin 53226, USA.
Abstract:
Cancer cell overexpresses numerus proteins, however, how these up-regulated proteins, especially those enzymatically opposite kinases and phosphatases, act together to promote oncogenesis is unknown. Here, we reported that protein tyrosine phosphatase H1 (PTPH1) is a scaffold protein for receptor tyrosine kinase (HER2) to potentiate breast tumorigenesis. PTPH1 utilizes its PDZ domain to bind HER2, p38γ, PBK, and YAP1 and to increase HER2 nuclear translocation, stemness, and oncogenesis. PTPH1 de-phosphorylates HER2 and reciprocally increases HER2 protein expression dependent on cellular content. PTPH1 itself can be phosphorylated at S459 by redundant kinases p38γ and/or PBK, thereby distinctively regulating expression and/or turnover of scaffold proteins. Moreover, PTPH1 and HER2 cooperate to increase PBK and Yap1 transcription thus acting as an additional mechanism to activate the scaffold. PTPH1 protein levels are higher in HER2+ breast cancer in which their phosphorylated forms are inversely correlated, indicating an integrated oncogenic activity through coordinated PTPH1 phosphorylation and HER2 de-phosphorylation. Combinational, but not individual, application of scaffold-kinases' inhibitors suppresses xenograft growth in mice. Thus, a PDZ-coupled and phosphorylation-driven scaffold can integrate proliferative signaling of enzymatically distinct proteins as a super-oncogene and as a target for combination therapy.
Insights
Protein tyrosine phosphatase H1 (PTPH1) acts as a scaffold protein, binding HER2 to promote breast cancer. Inhibiting PTPH1 and HER2 together suppressed tumor growth, revealing a potential combination therapy target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cancer cells overexpress numerous proteins, but the interplay between opposing enzymes like kinases and phosphatases in oncogenesis remains unclear.
- Understanding how these proteins cooperate is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the role of protein tyrosine phosphatase H1 (PTPH1) as a scaffold protein in HER2-positive breast tumorigenesis.
- To elucidate the molecular mechanisms by which PTPH1 integrates signaling pathways to promote cancer growth.
Main Methods:
- Utilized PDZ domain interactions to bind HER2, p38γ, PBK, and YAP1.
- Investigated PTPH1 phosphorylation at S459 by p38γ and/or PBK.
- Analyzed PTPH1 and HER2 cooperation in regulating PBK and YAP1 transcription.
- Assessed PTPH1 and HER2 protein levels in HER2+ breast cancer.
- Evaluated the efficacy of combinational scaffold-kinase inhibitors in xenograft mouse models.
Main Results:
- PTPH1 binds HER2, increasing its nuclear translocation, stemness, and oncogenesis.
- PTPH1 de-phosphorylates HER2, enhancing its protein expression.
- PTPH1 phosphorylation at S459 by p38γ/PBK regulates scaffold protein expression/turnover.
- PTPH1 and HER2 co-activate PBK and YAP1 transcription.
- Higher PTPH1 levels and inverse correlation of phosphorylated forms in HER2+ breast cancer indicate integrated oncogenic activity.
- Combined inhibition of scaffold-kinases suppressed tumor growth in mice.
Conclusions:
- PTPH1 functions as a crucial scaffold protein integrating distinct signaling pathways (HER2, p38γ, PBK, YAP1) in breast tumorigenesis.
- This PDZ-coupled, phosphorylation-driven scaffold acts as a super-oncogene.
- Coordinated PTPH1 phosphorylation and HER2 de-phosphorylation represent a key mechanism in HER2+ breast cancer.
- Combinational therapy targeting PTPH1 and associated kinases shows promise for treating breast cancer.
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