Targeting the non‐ATP‐binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T‐cell lymphoma (CTCL)

Zhang, Xu Hannah; Chen, Chih-Hong; Zhang, Lipeng; Hsiang, Jack; Wu, Xiwei; Hu, Weidong; Horne, David; Nam, Sangkil; Shively, J. E.; Rosen, Steven T.

doi:10.1002/1873-3468.14186

Cited by 8 publications

(12 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In both these structures the αG-helices interaction is very similar, as well as the relative orientation of the kinases. Several studies have shown that small molecules can target this region (32)(33)(34)(35)(36) and modulate the position of the MAPK insert helices (Fig. S6).…”

Section: Engagement With Substratementioning

confidence: 99%

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Juyoux¹,

Galdadas

Gobbo

et al. 2022

Preprint

View full text Add to dashboard Cite

The MAP kinase p38α is a central component of signalling in inflammation and the immune response, and is therefore an important drug target. Little is known about the molecular mechanism of its activation by double-phosphorylation from MAP2Ks, due to the challenge of trapping a transient and dynamic hetero-kinase complex. Here, we applied a multidisciplinary approach to generate the first structure of p38α in complex with its MAP2K MKK6 and understand the activation mechanism. Integrating cryo-EM with MD simulations and in cellulo experiments, we demonstrate a dynamic, multi-step, phosphorylation mechanism, reveal new catalytically relevant interactions, and show that MAP2K disordered N-termini determine pathway specificity. Our work captures, for the first time, a fundamental step of cell signalling: a kinase phosphorylating its downstream target kinase.

show abstract

Section: Engagement With Substratementioning

confidence: 99%

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Juyoux¹,

Galdadas

Gobbo

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…p38γ MAPK has been shown to regulate cell cycle transition, cell mobility, metastasis, EMT, CSC population, and tumorigenesis ( 10 , 36 – 39 ). Importantly, p38γ MAPK is overexpressed and implicated in several types of cancers including colorectal cancer, liver cancer, pancreatic cancer, and breast cancer ( 16 , 37 , 40 , 41 ); increased p38γ MAPK expression predicts a poor clinical prognosis ( 18 , 36 ). CSCs are a subpopulation of tumor cells capable of self-renewal and differentiation and involved in tumor initiation, recurrence, progression, chemoresistance and metastasis ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

Li,

Xu,

Chen

et al. 2024

Front. Oncol.

View full text Add to dashboard Cite

PurposeAlcohol consumption increases the risk of breast cancer and promotes cancer progression. Alcohol exposure could affect both processes of the mammary carcinogenesis, namely, the cell transformation and onset of tumorigenesis as well as cancer aggressiveness including metastasis and drug resistance/recurrence. However, the cellular and molecular mechanisms underlying alcohol tumor promotion remain unclear. There are four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family, namely, p38α, p38β, p38γ and p38δ. We have previously demonstrated alcohol exposure selectively activated p38γ MAPK in breast cancer cells in vitro and in vivo. Pirfenidone (PFD), an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis, is also a pharmacological inhibitor of p38γ MAPK. This study aimed to determine whether PFD is useful to inhibit alcohol-induced promotion of breast cancer.MethodsFemale adolescent (5 weeks) MMTV-Wnt1 mice were exposed to alcohol with a liquid diet containing 6.7% ethanol. Some mice received intraperitoneal (IP) injection of PFD (100 mg/kg) every other day. After that, the effects of alcohol and PFD on mammary tumorigenesis and metastasis were examined.ResultsAlcohol promoted the progression of mammary tumors in adolescent MMTV-Wnt1 mice. Treatment of PFD blocked tumor growth and alcohol-promoted metastasis. It also significantly inhibited alcohol-induced tumorsphere formation and cancer stem cell (CSC) population.ConclusionPFD inhibited mammary tumor growth and alcohol-promoted metastasis. Since PFD is an FDA-approved drug, the current findings may be helpful to re-purpose its application in treating aggressive breast cancer and alcohol-promoted mammary tumor progression.

show abstract

“…In both these structures, the αG-helices interaction is very similar, as well as the relative orientation of the kinases. Several studies have shown that small molecules can target this region in p38 isoforms ( 37 – 41 ) and modulate the position of the MAPK-insert helices (fig. S7).…”

Section: Discussionmentioning

confidence: 99%

“…2, A, C, and D, and movie S2), which clamps the MKK6 αG helix upon binding (movie S3). This insert has been described as a lipid-binding site important in regulation ( 35 , 36 ), and several studies have identified small molecules that target this pocket ( 37 – 41 ) (fig. S7).…”

Section: Architecture Of the Mkk6-p38α Complexmentioning

confidence: 99%

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Juyoux,

Galdadas,

Gobbo

et al. 2023

Science

View full text Add to dashboard Cite

The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo–electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase.

show abstract

Targeting the non‐ATP‐binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T‐cell lymphoma (CTCL)

Cited by 8 publications

References 65 publications

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Pirfenidone ameliorates alcohol-induced promotion of breast cancer in mice

Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation

Contact Info

Product

Resources

About