Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism

Chen, Ming; Wan, Lixin; Zhang, Jiangwen; Zhang, Jinfang; Mendez, Lourdes M.; Clohessy, John G.; Berry, Kelsey; Victor, Joshua; Yin, Qian; Zhu, Yong‐Guan; Wei, Wenyi; Pandolfi, Pier Paolo

doi:10.1038/s41467-017-02272-y

Cited by 45 publications

(36 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RAF kinases are the important upstream MAPK activators (Chen et al, ) and are known as RAS effectors (Ambrogio et al, ). RAF gene encodes ARAF , BRAF, and CRAF (or RAF1 ) (Sanclemente et al, ), and its activation in cancer cells requires RAF dimerization that is possibly assisted by RAS dimerization (Ambrogio et al, ).…”

Section: Mapk Signalingmentioning

confidence: 99%

“…Acquiring activating mutations and dephosphorylation of RAF inhibitory sites mediated by phosphatases like protein phosphatase 1α (PP1α) are responsible for reactivation of this kinase (Chen et al, ). BRAF mutations in metastatic cancers confer worse prognosis leading to an increase in the rate of mortality relative to the wild‐type BRAF.…”

Section: Mapk Signalingmentioning

confidence: 99%

“…ERK activation in a negative or positive loop is able to either suppress (Yen et al, ) or activate BRAF activity. This activation is mediated through ERK inducible effect on S6K/PP1α (Chen et al, ). ERK blockade can be useful for overcoming or delaying resistance mechanisms to inhibitors of upstream kinases including BRAF and MEK beneficial for a broader population of cancer patients (Sullivan et al, ) (Figures A and A).…”

Section: Mapk Signalingmentioning

confidence: 99%

“…Co‐activation of MAPK and PI3K/AKT pathways is common in cancer (Chen et al, ). PI3K reactivation is a common mechanism of acquired cancer cell resistance to therapy, and PI3K inhibitors can be used as a promising strategy for cancer cell sensitization to MAPK‐targeted therapies (Yan et al, ; Yen et al, ).…”

Section: Mapk Cross‐talking With Other Signaling Pathwaysmentioning

confidence: 99%

See 3 more Smart Citations

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

View full text Add to dashboard Cite

Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-β, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

show abstract

Section: Mapk Signalingmentioning

confidence: 99%

Section: Mapk Signalingmentioning

confidence: 99%

Section: Mapk Signalingmentioning

confidence: 99%

Section: Mapk Cross‐talking With Other Signaling Pathwaysmentioning

confidence: 99%

See 2 more Smart Citations

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

View full text Add to dashboard Cite

show abstract

“…Phospho-AKT then activates different substrates, such as the mammalian target of rapamycin (mTOR) 40 , which is a serine/threonine kinase that regulates cell growth, survival, and proliferation. More recently, it was shown that the simultaneous activation of the mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways occurs in co-deleted PTEN and promyelocytic leukemia protein (PML) human metastatic prostate cancer 41 .…”

Section: Pten Functions In the Cytoplasm And Nucleusmentioning

confidence: 99%

Caracterização do genoma e da resposta imune no microambiente tumoral de neoplasias PTEN-deficientes

Vidotto¹

View full text Add to dashboard Cite

is my second PhD supervisor. By virtue of her inspiration, this study now touches both immunology and genetic fields. During my 8-months stay in Kingston, Dr. Madhuri was extraordinary kind and open to discuss the several-and sometimes too manyquestions I had. During my internship with her, I was also able to learn a bit more about her culture and how similar Brazilian and Indians can be. In addition, she gave me several opportunities for bioinformatics training, which was crucial for the development of this thesis and other future partnerships. Dr. Madhuri, thank you for being so kind and helpful during the three years of my PhD. Aos grandes colaboradores e mentes inspiradoras por trás de grandes aprendizados: Dr. Fabiano Saggioro, por ter trabalhado duro comigo durante sábados, domingos e feriados e por partilhar comigo a sua visão de mundo descontraída e humilde. Dr. Fabiano também foi peça chave na seleção e análise dos pacientes desse estudo; ao Dr. Rodolfo B. Reis, por ter contribuído para a obtenção dos casos desse estudo e por ser extremamente motivado em mudar a realidade da ciência e medicina no Brasil; ao Dr. Daniel Tiezzi, por prontamente responder meus e-mails inadequados durante fins de semana e feriados e por sempre me ajudar em alguma questão de bioinformática que eu tinha. Dr. Daniel me inspirou a sempre aprender cada vez mais. Tê-lo como colaborador nesse estudo é um orgulho! Agradeço também a Dra. Lúcia Martelli, que fez parte da minha rotina de aprendizado e que sempre transmitiu extrema sabedoria para lidar com problemas que, para mim, pareciam complicados demais. A agradeço, além de tudo, por sempre dar sua opinião prática sobre como eu deveria apresentar meus resultados para uma banca.

show abstract

H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen‐Activated Protein Kinase–Dependent Manner and Sponging microRNA 200b‐3p

et al. 2021

View full text Add to dashboard Cite

Background and Aims Bone is the second most frequent site of metastasis for HCC, which leads to an extremely poor prognosis. HCC bone metastasis is typically osteolytic, involving the activation of osteoclasts. Long noncoding RNA H19 plays an important role in the pathogenesis of human cancers. Nonetheless, the mechanism underlying the participation of H19 in HCC bone metastasis remains unclear. Approach and Results The current study established a mouse HCC bone metastasis model by using serial intracardiac injection and cell isolation to obtain cells with distinct bone metastasis ability. H19 was highly expressed in these cells and in clinical HCC bone metastasis specimens. Both osteoclastogenesis in vitro and HCC bone metastasis in vivo were promoted by H19 overexpression, whereas these processes were suppressed by H19 knockdown. H19 overexpression attenuated p38 phosphorylation and further down‐regulated the expression of osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor. However, up‐regulated OPG expression as well as suppressed osteoclastogenesis caused by H19 knockdown were recovered by p38 interference, indicating that p38 mitogen‐activated protein kinase (MAPK)–OPG contributed to H19‐promoted HCC bone metastasis. Furthermore, we demonstrated that H19 inhibited the expression of OPG by binding with protein phosphatase 1 catalytic subunit alpha (PPP1CA), which dephosphorylates p38. SB‐203580‐mediated inactivation of p38MAPK reversed the down‐regulation of HCC bone metastasis caused by H19 knockdown in vivo. Additionally, H19 enhanced cell migration and invasion by up‐regulating zinc finger E‐box binding homeobox 1 through the sequestration of microRNA (miR) 200b‐3p. Conclusions H19 plays a critical role in HCC bone metastasis by reducing OPG expression, which is mediated by the PPP1CA‐induced inactivation of the p38MAPK pathway; and H19 also functions as a sponge for miR‐200b‐3p.

show abstract

Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism

Cited by 45 publications

References 58 publications

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Caracterização do genoma e da resposta imune no microambiente tumoral de neoplasias PTEN-deficientes

H19 Promotes HCC Bone Metastasis Through Reducing Osteoprotegerin Expression in a Protein Phosphatase 1 Catalytic Subunit Alpha/p38 Mitogen‐Activated Protein Kinase–Dependent Manner and Sponging microRNA 200b‐3p

Contact Info

Product

Resources

About