HPIP is an essential scaffolding protein running through the EGFR-RAS-ERK pathway and drives tumorigenesis

Jiang, Qiwei; Zhang, Deyu; Liu, Juan; Liang, Chaoyang; Yang, Ronghui; Zhang, Cheng; Wu, Jun; Lin, Jing; Ye, Tianxing; Ding, Lihua; Li, Jianbin; Gao, Shan; Li, Binghui; Ye, Qinong

doi:10.1126/sciadv.ade1155

Cited by 4 publications

(1 citation statement)

References 56 publications

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“…First, HPIP associates with EGFR, SHC, Grb2, SOS1, RAS, RAF, and MEK to form complex 1. Subsequently, the scaffold leaves behind a few upstream components to bind ERK and make complex 2 with SHC, RAS, RAF, MEK, and ERK [422]. Further research is needed to fully understand the importance of this little-studied scaffold in health, disease, and potential therapeutic implications.…”

Section: Hpipmentioning

confidence: 99%

Navigating the ERK1/2 MAPK Cascade

Martin-Vega,

Cobb

2023

Biomolecules

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The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all cell types. Notably, ERK1/2 are implicated in specific processes in a context-dependent manner as in stem cells and pancreatic β-cells. Alterations in the different components of this cascade result in dysregulation of the effector kinases ERK1/2 which communicate with hundreds of substrates. Aberrant activation of the pathway contributes to a range of disorders, including cancer. This review provides an overview of the structure, activation, regulation, and mutational frequency of the different tiers of the cascade; with a particular focus on ERK1/2. We highlight the importance of scaffold proteins that contribute to kinase localization and coordinate interaction dynamics of the kinases with substrates, activators, and inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues in this field.

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Section: Hpipmentioning

confidence: 99%

Navigating the ERK1/2 MAPK Cascade

Martin-Vega,

Cobb

2023

Biomolecules

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Functional loss of ERBB receptor feedback inhibitor 1 (MIG6) promotes glioblastoma tumorigenesis by aberrant activation of epidermal growth factor receptor (EGFR)

Yi,

Cho,

Kim

et al. 2024

Molecular Oncology

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Dysregulation of epidermal growth factor receptor (EGFR) is one of the most common mechanisms associated with the pathogenesis of various cancers. Mitogen‐inducible gene 6 [MIG6; also known as ERBB receptor feedback inhibitor 1 (ERRFI1)], identified as a feedback inhibitor of EGFR, negatively regulates EGFR by directly inhibiting its kinase activity and facilitating its internalization, subsequently leading to degradation. Despite its proposed role as an EGFR‐dependent tumor suppressor, the functional consequences and clinical relevance in cancer etiology remain incompletely understood. Here, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR‐dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. We propose that the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR‐targeted cancer therapies, including glioblastoma.

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Phosphorylation determines the glucose metabolism reprogramming and tumor-promoting activity of sine oculis homeobox 1

Lin,

Li,

Yuan

et al. 2024

Sig Transduct Target Ther

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Aerobic glycolysis is a hallmark of cancer and is regulated by growth factors, protein kinases and transcription factors. However, it remains poorly understood how these components interact to regulate aerobic glycolysis coordinately. Here, we show that sine oculis homeobox 1 (SIX1) phosphorylation integrates growth factors (e.g. TGFβ, EGF) to control aerobic glycolysis and determines its tumor-promoting activity. SIX1 is phosphorylated at serine 225 (S225) by growth factors-activated protein kinases ERK1/2 and its phosphorylation is responsible for glycolysis stimulated by some growth factors. SIX1 is dephosphorylated by the atypical protein phosphatase eyes absent 4 (EYA4). Phosphorylation blocks non-canonical ubiquitination and degradation of SIX1 through the E3 ubiquitin ligase FZR1. Unexpectedly, the non-canonical phosphorylation mimic SIX1 (S225K), but not the canonical phosphorylation mimic SIX1 (S225D/E), phenocopies the effects of SIX1 phosphorylation on glycolysis and cancer cell growth and metastasis in vitro and in mice. Compared to normal liver tissues, SIX1 phosphorylation at S225 (pS225) is upregulated in human liver cancer tissues. ERK1/2 expression is positively correlated with pS225 and EYA4 expression is negatively associated with pS225 in liver cancer specimens. Moreover, low expression of pS225 had longer disease-free survival and overall survival in patients with liver cancer. Thus, we identify a common mechanism underlying growth factors-mediated glycolysis, and provide a previously unidentified mode for non-classical phosphorylation mimics of a protein. Targeting growth factors/SIX1 signaling pathway may be beneficial to cancer treatment.

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HPIP is an essential scaffolding protein running through the EGFR-RAS-ERK pathway and drives tumorigenesis

Cited by 4 publications

References 56 publications

Navigating the ERK1/2 MAPK Cascade

Navigating the ERK1/2 MAPK Cascade

Functional loss of ERBB receptor feedback inhibitor 1 (MIG6) promotes glioblastoma tumorigenesis by aberrant activation of epidermal growth factor receptor (EGFR)

Phosphorylation determines the glucose metabolism reprogramming and tumor-promoting activity of sine oculis homeobox 1

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