The Abl/Abi signaling links WAVE regulatory complex to Cbl E3 ubiquitin ligase and is essential for breast cancer cell metastasis.

The family of Abelson interactor (Abi) proteins is a component of WAVE regulatory complex (WRC) and a downstream target of Abelson (Abl) tyrosine kinase. The fact that Abi proteins also interact with diverse membrane proteins and intracellular signaling molecules places these proteins at a central position in the network that controls cytoskeletal functions and cancer cell metastasis. Here, we identified a motif in Abi proteins that conforms to consensus sequences found in a cohort of receptor and non-receptor tyrosine kinases that bind to Cbl-tyrosine kinase binding domain. The phosphorylation of tyrosine 213 in this motif is essential for Abi degradation. Double knockout of c-Cbl and Cbl B in Bcr-Abl-transformed leukemic cells abolishes Abi1, Abi2, and WAVE2 degradation. Moreover, knockout of Abi1 reduces Src family kinase Lyn activation in Bcr-Abl-positive leukemic cells and promotes EGF-induced EGF receptor downregulation in breast cancer cells. Importantly, Abi1 depletion impeded breast cancer cell invasion in vitro and metastasis in mouse xenografts. Together, these studies uncover a novel mechanism by which the WRC and receptor/non-receptor tyrosine kinases are regulated and identify Abi1 as a potential therapeutic target for metastatic breast cancer.

Spectrum of Movement Disorders in Patients With Neuroinvasive West Nile Virus Infection.

BACKGROUND: West Nile virus (WNV) is a flavivirus that is recognized as one of the common causes of arboviral neurological disease in the world. WNV infections usually manifest with constitutional symptoms such as fever, fatigue, myalgia, rash, arthralgia, and headache. Neuroinvasive WNV infections are characterized by signs and symptoms suggestive of meningitis, encephalitis, meningoencephalitis, and acute flaccid paralysis. In addition, many patients with neuroinvasive WNV infection develop a wide range of movement disorders. This article aims to comprehensively review the spectrum and natural course of the movement disorders observed in patients with neuroinvasive WNV infections. METHODS: A literature search was performed in March 2019 (in PubMed and EMBASE) to identify articles for this review. RESULTS: Movement disorders observed in the context of WNV infections include tremor, opsoclonus-myoclonus, parkinsonism, myoclonus, ataxia, and chorea. Most often, these movement disorders resolve within a few weeks to months with an indolent course. The commonly observed tremor phenotypes include action tremor of the upper extremities (bilateral > unilateral). Tremor in patients with West Nile meningitis subsides earlier than that in patients with West Nile encephalitis/acute flaccid paralysis. Opsoclonus-myoclonus in WNV infections responds well to intravenous immunoglobulins/plasmapheresis/corticosteroids. Parkinsonism has been reported to be mild in nature and usually lasts for a few weeks to months in the majority of the patients. CONCLUSION: A wide spectrum of movement disorders is observed in neuroinvasive WNV infections. Longitudinal studies are warranted to obtain better insights into the natural course of these movement disorders.