2. Academic Validation
  3. Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression

Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression

  • Cell Commun Signal. 2024 Feb 12;22(1):115. doi: 10.1186/s12964-024-01487-z.
Yujiao Deng # 1 2,  Zhanwu Hou # 3,  Yizhen Li # 2,  Ming Yi 4,  Ying Wu 2,  Yi Zheng 2,  Fei Yang 3,  Guansheng Zhong 4,  Qian Hao 2,  Zhen Zhai 2,  Meng Wang 2,  Xiaobin Ma 2,  Huafeng Kang 2,  Fanpu Ji 5,  Chenfang Dong 6 7,  Huadong Liu 8,  Zhijun Dai 9 10
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Center for Mitochondrial Biology and Medicine & Douglas C. Wallace Institute for Mitochondrial and Epigenetic Information Sciences, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 4 Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
  • 5 Department of Infectious Diseases, The Second Affiliated Hospital of Xian Jiaotong University, Xi'an, China.
  • 6 Department of Pathology and Pathophysiology, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 7 Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 8 Center for Mitochondrial Biology and Medicine & Douglas C. Wallace Institute for Mitochondrial and Epigenetic Information Sciences, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China. [email protected].
  • 9 Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. [email protected].
  • 10 Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 38347536 DOI: 10.1186/s12964-024-01487-z
Abstract

Phosphorylation proteomics is the basis for the study of abnormally activated kinase signaling pathways in breast Cancer, which facilitates the discovery of new oncogenic agents and drives the discovery of potential targets for early diagnosis and therapy of breast Cancer. In this study, we have explored the aberrantly active kinases in breast Cancer development and to elucidate the role of PRKCD_pY313 in triple negative breast Cancer (TNBC) progression. We collected 47 pairs of breast Cancer and paired far-cancer normal tissues and analyzed phosphorylated tyrosine (pY) Peptides by Superbinder resin and further enriched the phosphorylated serine/threonine (pS/pT) Peptides using TiO2 columns. We mapped the kinases activity of different subtypes of breast Cancer and identified PRKCD_pY313 was upregulated in TNBC cell lines. Gain-of-function assay revealed that PRKCD_pY313 facilitated the proliferation, enhanced invasion, accelerated metastasis, increased the mitochondrial membrane potential and reduced ROS level of TNBC cell lines, while Y313F mutation and low PRKCD_pY313 reversed these effects. Furthermore, PRKCD_pY313 significantly upregulated Src_pY419 and p38_pT180/pY182, while low PRKCD_pY313 and PRKCD_Y313F had opposite effects. Dasatinib significantly inhibited the growth of PRKCD_pY313 overexpression cells, and this effect could be enhanced by Adezmapimod. In nude mice xenograft model, PRKCD_pY313 significantly promoted tumor progression, accompanied by increased levels of Ki-67, Bcl-xL and Vimentin, and decreased levels of Bad, cleaved Caspase 3 and ZO1, which was opposite to the trend of Y313F group. Collectively, the heterogeneity of phosphorylation exists in different molecular subtypes of breast Cancer. PRKCD_pY313 activates Src and accelerates TNBC progression, which could be inhibited by Dasatinib.

Keywords

Breast cancer; Kinase activity; PRKCD; Phosphoproteomic; Src.

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