The non-canonical Hippo/Mst pathway in lymphocyte development and functions

Du, Xingrong; Yu, Alan; Tao, Wufan

doi:10.1093/abbs/gmu112

Cited by 24 publications

(22 citation statements)

References 42 publications

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“…In this perspective, the Hippo pathway, a key regulator of immunological homeostasis appears to influence significant steps during initiation or progression of various patho-physiological conditions31. Interestingly, role of Hippo signaling during mycobacterial infection of the host immune cells and subsequent manifestations towards disease progression is not known.…”

Section: Resultsmentioning

confidence: 99%

“…Originally identified in Drosophila to promote apoptosis24, inhibit cell proliferation and tumorigenesis2325; Hippo signaling components are now being implicated in T-cell deficiency associated with viral, bacterial and fungal infections26272829 and also in autoimmune manifestations30. MST1/2 deficient mice were reported to have hypoplastic lymphoid organs because of defective T cell migration3031. It was also shown that MST2 deficient mice produce decreased levels of proinflammatory cytokines and chemokine CCL2 during the process of retinal detachment32.…”

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confidence: 99%

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Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

Boro

Singh

Balaji

2016

Sci Rep

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Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20–like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

Boro

Singh

Balaji

2016

Sci Rep

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“…In the context of the immune system, a non-canonical, Hippo/MST pathway is emerging as a central orchestrator of T cells activities, being implicated in an array of functions spanning from T cells development and activation to survival and trafficking. 13 Another level of regulation of core Hippo kinases refers to their cooperation with central nodes of the DNA damage response (DDR) machinery, chiefly the ataxia telangiectasia and Rad3-related protein (ATR)-Checkpoint kinase 1 (Chk1) and ataxia telangiectasia mutated (ATM)-Checkpoint Kinase 2 (Chk2) signaling avenues.…”

Section: Introductionmentioning

confidence: 99%

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Ercolani¹,

Benedetto²,

Terrenato

et al. 2017

Cancer Biology & Therapy

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The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2 nuc ) expression was significantly associated with nuclear expression of Chk1 (p D 0.046), whereas cytoplasmic pMST1/2 (pMST1/2 cyt ) expression was marginally associated with cytoplasmic TAZ staining (p D 0.053). Patients whose tumors expressed pMST1/2 nuc were at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2 cyt )seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.KEYWORDS HER2-positive breast cancer; Hippo pathway; LATS 1/2; MST1/2; triple-negative breast cancer

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“…This results in the cytoplasmic sequestration and degradation of YAP/TAZ, which inhibits YAP/TAZ-driven cell proliferation, survival, and migration. NDR1/2 are newly identified as members of the Hippo pathway (5,18,27), and were reported to play similar roles like LATS1/2 as upstream kinases of YAP (28)(29)(30)(31)(32)(33). Recent studies demonstrated critical functions of the Hippo signaling in innate immunity (17,24,34).…”

Section: Introductionmentioning

confidence: 99%

The Emerging Roles of NDR1/2 in Infection and Inflammation

Ong

et al. 2020

Front. Immunol.

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The nuclear Dbf2-related (NDR) kinases NDR1 and NDR2 belong to the NDR/LATS (large tumor suppressor) subfamily in the Hippo signaling pathway. They are highly conserved from yeast to humans. It is well-known that NDR1/2 control important cellular processes, such as morphological changes, centrosome duplication, cell proliferation, and apoptosis. Recent studies revealed that NDR1/2 also play important roles in the regulation of infection and inflammation. In this review, we summarized the roles of NDR1/2 in the modulation of inflammation induced by cytokines and innate immune response against the infection of bacteria and viruses, emphasizing on how NDR1/2 regulate signaling transduction through Hippo pathway-dependent and-independent manners.

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The non-canonical Hippo/Mst pathway in lymphocyte development and functions

Cited by 24 publications

References 42 publications

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

The Emerging Roles of NDR1/2 in Infection and Inflammation

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