Mammalian Sterile 20–like Kinase 1 Suppresses Lymphoma Development by Promoting Faithful Chromosome Segregation

Kim, Tae-Shin; Lee, Da-Hye; Kim, Sang Kyum; Shin, So Youn; Seo, Eul‐Ju; Lim, Dae–Sik

doi:10.1158/0008-5472.can-11-3956

Cited by 35 publications

(25 citation statements)

References 49 publications

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“…Although lymphoma has been described in STK4-deficit mouse, our patient is the first human with this mutation-developed lymphoma. [12] MALT lymphoma is a low-grade B-cell lymphoma of mucosa associated with lymphoid tissue and arises in a number of epithelial tissues, including conjunctiva, salivary gland, thyroid gland, stomach, liver, small bowel, lung and urogenital tract. [13] It constitutes about 5% of all non-Hodgkin lymphomas and almost 50% of all gastric lymphomas in adults.…”

Section: Discussionmentioning

confidence: 99%

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4‐Mutated CD4+ Lymphocytopenia

Lum

Bonney

Cheesman

et al. 2016

Pediatric Blood & Cancer

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Idiopathic CD4+ lymphocytopenia and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are rare diseases in children. We report the first case of a child with STK4-mutated CD4+ lymphocytopenia who developed Epstein-Barr virus associated MALT lymphoma arising in the salivary gland. The child achieved complete remission with rituximab, and her immunodeficiency was cured by haematopoietic stem cell transplantation. The child remained well 24 months post transplantation.

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Section: Discussionmentioning

confidence: 99%

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4‐Mutated CD4+ Lymphocytopenia

Lum

Bonney

Cheesman

et al. 2016

Pediatric Blood & Cancer

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“…2/2 mice develop spontaneous tumors in liver, colon, and ethyl-N-nitrosoureainduced lymphomas/leukemias (14)(15)(16)(17)(18). Mst1 induces apoptosis through caspase-mediated proteolytic activation and histone H2B phosphorylation (19), or by enhancing Foxo1/3 nuclear entry through phosphorylation of Foxo1 and Foxo3 at S212 and S207, respectively, in fibroblasts and granule neurons (20,21).…”

Section: Mst2mentioning

confidence: 99%

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Shi

et al. 2014

The Journal of Immunology

122

126

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Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1−/− mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1−/− bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency–mediated human immunodeficiency syndrome.

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“…Recent studies have also demonstrated the role of Mst1/2 kinases in a YAPindependent mechanism, the so-called noncanonical Hippo pathway. For example, Mst1 suppresses lymphoma development by promoting faithful chromosome segregation, independently of YAP (18). Mst1/2 kinases also execute a variety of functions with multiple partners, such as Foxo1, Foxo3, Akt, and Aurora B, in different biological contexts (19)(20)(21)(22).…”

mentioning

confidence: 99%

Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis

Chung

Kim

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. Although several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using mammalian Hippo kinases (Mst1/2, mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1/2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings of YAP (Yes-associated protein)-mediated canonical Hippo signaling in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2 (forkhead box A2), which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that the mammalian Hippo kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2 rather than of YAP.non-canonical Hippo pathway | lung development P eripheral lung immaturity and deficiency of pulmonary surfactant cause many intractable pulmonary diseases. Deficit of surfactant because of preterm birth or genetic disorders of surfactant homeostasis induce respiratory distress syndrome (RDS) in the newborn period (1). Dysregulation of these genes also underlies the pathogenesis of many chronic lung diseases that have been considered idiopathic, such as interstitial lung disease, pulmonary alveolar proteinosis, and others (2). Elucidating the mechanism underlying regulation of surfactant would be very helpful for understanding the molecular basis of refractory lung diseases of both infants and adults.Alveoli are composed of type I and type II pneumocytes. The type II pneumocyte is the progenitor cell of the type I pneumocyte and plays a central role in physiological pulmonary functions, especially surfactant production (3). Type I pneumocytes contact alveolar capillaries and participate in gas exchange. Lung morphogenesis in mice is a dynamic process that can be divided into embryonic [embryonic day (E) 9-11.5], pseudoglandular (E11.5-16.5), canalicular (E16.5-17.5), saccular [E17.5 to postnatal (PN) day 5], and alveolar (PN5-28) stages. During canalicular and saccular stages in late gestation, peripheral lungs containing type I and II pneumocytes fully differentiate in preparation for postnatal respiration (4).Many transcription factors, including Foxa2 (forkhead...

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Mammalian Sterile 20–like Kinase 1 Suppresses Lymphoma Development by Promoting Faithful Chromosome Segregation

Cited by 35 publications

References 49 publications

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4‐Mutated CD4+ Lymphocytopenia

Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4‐Mutated CD4+ Lymphocytopenia

Mst1/Mst2 Regulate Development and Function of Regulatory T Cells through Modulation of Foxo1/Foxo3 Stability in Autoimmune Disease

Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis

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