Kinases in cerebral cavernous malformations: Pathogenesis and therapeutic targets

Cui, Qi; Bujaroski, Richard S.; Baell, Jonathan B.; Zheng, Xiangjian

doi:10.1016/j.bbamcr.2023.119488

Cited by 5 publications

(3 citation statements)

References 183 publications

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“…In addition to the value of mutational profiles helping patients and families better understanding the course of disease and the potential role of screening other family members, knowing the underlying molecular driver of disease may help with creation of targeted drug therapies – such as the current trials with mamalian target of rapamycin ( mTOR ) and KRAS inhibitors for AVM, and ROCK inhibitors for CCM [ 12 , 25 , 42 , 58 ]. The pharmacologic treatment of vascular lesions – including inhibition of growth, better control of existing malformations and possible prevention of recurrence after therapy – are exciting future areas of research in pediatric cerebrovascular neurosurgery.…”

Section: Advances In Molecular Biologymentioning

confidence: 99%

Pediatric Cerebral Vascular Malformations : Current and Future Perspectives

Smith

2024

J Korean Neurosurg Soc

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Intracranial vascular malformations typically encountered by pediatric neurosurgeons include arteriovenous malformations, vein of Galen malformations and cavernous malformations. While these remain amongst some of the most challenging lesions faced by patients and caregivers, the past decade has produced marked advances in the understanding of the pathophysiology of these conditions, with concomitant innovations in treatment. This article will highlight present and future perspectives relevant to these diseases, with a focus on an emerging approach utilizing disease-specific mutations to develop a novel taxonomy for these conditions.

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Section: Advances In Molecular Biologymentioning

confidence: 99%

Pediatric Cerebral Vascular Malformations : Current and Future Perspectives

Smith

2024

J Korean Neurosurg Soc

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“…b-blockers, such as propranolol, have been found to lower the risk of hemorrhage. 22,23 A large clinical controlled study demonstrated that propranolol can reduce the risk of rebleeding in patients with familial CMs. 24 Stereotactic radiotherapy.…”

Section: Treatment Of Cmsmentioning

confidence: 99%

Diagnosis and treatment status of suprasellar optic pathway cavernous malformations

Xu,

Yang

2023

J Int Med Res

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Cerebral cavernous malformations constitute a subtype of cerebral vascular malformation typically located in the cerebral cortex. However, their occurrence in the suprasellar optic pathway is relatively rare. There is some uncertainty surrounding the clinical diagnostic methods and optimal treatment strategies specific to suprasellar optic pathway cavernous malformations. In this narrative review, we retrospectively analyzed relevant literature related to suprasellar visual pathway cavernous malformations. We conducted a study involving 90 patients who were postoperatively diagnosed with cavernous malformations, including the 16-year-old male patient mentioned in this article. We have summarized crucial clinical data, including the patient age distribution, sex ratio, lesion locations, primary symptoms, and surgical approaches. The comprehensive analysis of this clinical information underscores the critical importance of timely intervention in relieving symptoms and improving neurological deficits in affected patients. These findings provide valuable guidance and insight for clinical practitioners and researchers dealing with this specific medical condition.

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“…The current thinking in the field (Snellings et al, 2021) (Qi et al, 2023;Valentino et al, 2021) is that the CCM complex is required to negatively regulate Mitogen Activated Protein Kinase Kinase Kinase 3 (MAP3K3/MEKK3). The molecular mechanism by which MAP3K3 is regulated is unknown, although a physical interaction between CCM2 and MAP3K3 has been detected (Fisher et al, 2015;Wang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The Ccm3-GckIII signaling axis regulates Rab11-dependent recycling to the apical compartment

Burguete,

Song,

Ghabrial

2024

Preprint

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Kinase cascades underlie many signaling pathways and are key regulators of development and morphogenesis. We have characterized a Hippo-like kinase cascade consisting of Thousand and One kinase (Tao), Germinal Center Kinase III (GckIII/Wheezy), and Tricornered (Trc) that plays an essential role in morphogenesis of tracheal terminal cell tubes in Drosophila. In this cascade, GckIII is the central kinase and is thought to act together with its binding partner, Cerebral Cavernous Malformations 3 (Ccm3). As suggested by its name, Drosophila Ccm3 is the ortholog of a human vascular disease gene. As such, defining the Ccm3 pathway is critical to understanding both normal development and disease. Here we generate and characterize a null allele of Ccm3 in Drosophila. We uncover a maternal contribution of Ccm3 to embryonic development, show that maternal/zygotic null embryos have defective multicellular tracheal tubes, and that tracheal terminal cells derived from zygotic clones that also lack maternal Ccm3, show fully penetrant tube dilation defects identical to those we previously described for other pathway genes. We show that wildtype Ccm3 colocalizes with p-GckIII during early embryogenesis, and that in larval terminal cells, is found in the nucleus as well as associated with the apical membrane. We further demonstrate that Mouse protein 25 (Mo25), known to encode a protein that binds and stabilizes GckIII proteins in the active conformation, is required to prevent Ccm3-like tube dilations, showing that Mo25 and Ccm3, together with Tao, are required to fully activate GckIII, which directly phosphorylates and activates Tricornered (Trc). We show that this Ccm3 signaling cassette operates in other epithelial tissues such as the wing, and in non-epithelial tissues such as motor neurons. Lastly, we define a role of Ccm3-GckIII signaling in the distribution of active Rab11, leading us to propose that persistent local Rab11 activity results in elevated recycling of membrane and apical determinants to the apical domain, and consequent dilation of tubes. We validate this model by showing that loss of Rab11 activity ameliorates the tube dilation defects of pathway mutants.

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Kinases in cerebral cavernous malformations: Pathogenesis and therapeutic targets

Cited by 5 publications

References 183 publications

Pediatric Cerebral Vascular Malformations : Current and Future Perspectives

Pediatric Cerebral Vascular Malformations : Current and Future Perspectives

Diagnosis and treatment status of suprasellar optic pathway cavernous malformations

The Ccm3-GckIII signaling axis regulates Rab11-dependent recycling to the apical compartment

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