Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1

Song, Jianguo; Wang, Tianzhuo; Chi, Xiaochun; Wei, Xiaofan; Xu, Sidi; Yu, Miao; He, Huiying; Ma, Ji; Li, Xueying; Du, Juan; Sun, Xiaoran; Wang, Yunling; Zhan, Jun; Zhang, Hongquan

doi:10.1016/j.celrep.2019.11.035

Cited by 46 publications

(40 citation statements)

References 48 publications

(61 reference statements)

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“…Therefore, YAP could not be activated, and non-phosphorylated YAP would be translocated into the nucleus where it would activate target gene transcription together with TEA domain family members (TEADs). Therefore, our findings were distinct from those of Guo et al in MSCs 29 and of Song et al in kidney cells 28 . Our study suggested that the regulatory effect of Kindlin-2 on Hippo signaling may vary in different cell types.…”

Section: Discussioncontrasting

confidence: 99%

“…However, the latter study did not elucidate the functions of YAP and TAZ in SCs. We demonstrated previously that Kindlin-2 played a critical role in regulation of the Hippo/YAP signaling pathway by complexing with LATS1 and MOB1 in kidney cells 28 . In this study, as a novel mechanism of modulation of YAP phosphorylation, we showed that Kindlin-2 isolates LATS1 from closing to the WW domain of YAP and impedes binding of the LATS1 kinase domain to YAP (Fig.…”

Section: Discussionmentioning

confidence: 86%

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Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice

et al. 2021

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Kindlin-2 is known to play important roles in the development of mesoderm-derived tissues including myocardium, smooth muscle, cartilage and blood vessels. However, nothing is known for the role of Kindlin-2 in mesoderm-derived reproductive organs. Here, we report that loss of Kindlin-2 in Sertoli cells caused severe testis hypoplasia, abnormal germ cell development and complete infertility in male mice. Functionally, loss of Kindlin-2 inhibits proliferation, increases apoptosis, impairs phagocytosis in Sertoli cells and destroyed the integration of blood-testis barrier structure in testes. Mechanistically, Kindlin-2 interacts with LATS1 and YAP, the key components of Hippo pathway. Kindlin-2 impedes LATS1 interaction with YAP, and depletion of Kindlin-2 enhances LATS1 interaction with YAP, increases YAP phosphorylation and decreases its nuclear translocation. For clinical relevance, lower Kindlin-2 expression and decreased nucleus localization of YAP was found in SCOS patients. Collectively, we demonstrated that Kindlin-2 in Sertoli cells is essential for sperm development and male reproduction.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 86%

Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice

et al. 2021

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“…In Mus musculus, MmMOB1 functions as a tumor suppressor and tissue homeostasis factor as a member of Hippo signaling, namely by controlling apoptotic signaling in keratinocytes [10,[37][38][39]. MmMOB1 also participates in renal homeostasis, MmMOB1 mediated Hippo activation, through MmLATS1 and MmYAP phosphorylation, is associated with diminished renal fibrosis [40]. The Wnt (wingless integrated) pathway is also activated but seems to have an opposite association.…”

Section: Tissue Homeostasis: Mob As Regulators Of Cell Proliferation and Apoptosismentioning

confidence: 99%

MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis

Delgado

Carmona

Nolasco

et al. 2020

Biology

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The MOB family proteins are constituted by highly conserved eukaryote kinase signal adaptors that are often essential both for cell and organism survival. Historically, MOB family proteins have been described as kinase activators participating in Hippo and Mitotic Exit Network/ Septation Initiation Network (MEN/SIN) signaling pathways that have central roles in regulating cytokinesis, cell polarity, cell proliferation and cell fate to control organ growth and regeneration. In metazoans, MOB proteins act as central signal adaptors of the core kinase module MST1/2, LATS1/2, and NDR1/2 kinases that phosphorylate the YAP/TAZ transcriptional co-activators, effectors of the Hippo signaling pathway. More recently, MOBs have been shown to also have non-kinase partners and to be involved in cilia biology, indicating that its activity and regulation is more diverse than expected. In this review, we explore the possible ancestral role of MEN/SIN pathways on the built-in nature of a more complex and functionally expanded Hippo pathway, by focusing on the most conserved components of these pathways, the MOB proteins. We discuss the current knowledge of MOBs-regulated signaling, with emphasis on its evolutionary history and role in morphogenesis, cytokinesis, and cell polarity from unicellular to multicellular organisms.

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“…Co‐localization of praja2•PKA complexes with PKA substrate/effector molecules ensures efficient integration and propagation of the locally generated cAMP to distinct target sites (Lignitto et al, 2011a). praja2 acts as an E3 ubiquitin ligase that controls ubiquitylation and stability of colocalized signalling enzymes, including PKA, adapter proteins and tumour suppressors (Lignitto et al, 2011b; Lignitto et al, 2013; Sepe et al, 2014; Zhang et al, 2015; Rinaldi et al, 2016; Song et al, 2019). PKA regulates different aspects of cilium biology.…”

Section: Introductionmentioning

confidence: 99%

The TBC1D31/praja2 complex controls primary ciliogenesis through PKA‐directed OFD1 ubiquitylation

Senatore¹,

Chiuso²,

Rinaldi³

et al. 2021

The EMBO Journal

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The primary cilium is a microtubule‐based sensory organelle that dynamically links signalling pathways to cell differentiation, growth, and development. Genetic defects of primary cilia are responsible for genetic disorders known as ciliopathies. Orofacial digital type I syndrome (OFDI) is an X‐linked congenital ciliopathy caused by mutations in the OFD1 gene and characterized by malformations of the face, oral cavity, digits and, in the majority of cases, polycystic kidney disease. OFD1 plays a key role in cilium biogenesis. However, the impact of signalling pathways and the role of the ubiquitin‐proteasome system (UPS) in the control of OFD1 stability remain unknown. Here, we identify a novel complex assembled at centrosomes by TBC1D31, including the E3 ubiquitin ligase praja2, protein kinase A (PKA), and OFD1. We show that TBC1D31 is essential for ciliogenesis. Mechanistically, upon G‐protein‐coupled receptor (GPCR)‐cAMP stimulation, PKA phosphorylates OFD1 at ser735, thus promoting OFD1 proteolysis through the praja2‐UPS circuitry. This pathway is essential for ciliogenesis. In addition, a non‐phosphorylatable OFD1 mutant dramatically affects cilium morphology and dynamics. Consistent with a role of the TBC1D31/praja2/OFD1 axis in ciliogenesis, alteration of this molecular network impairs ciliogenesis in vivo in Medaka fish, resulting in developmental defects. Our findings reveal a multifunctional transduction unit at the centrosome that links GPCR signalling to ubiquitylation and proteolysis of the ciliopathy protein OFD1, with important implications on cilium biology and development. Derangement of this control mechanism may underpin human genetic disorders.

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Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1

Cited by 46 publications

References 48 publications

Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice

Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice

MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis

The TBC1D31/praja2 complex controls primary ciliogenesis through PKA‐directed OFD1 ubiquitylation

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