Differential regulation of axonal growth and neuromuscular junction assembly by HGF/c‐Met signaling

Li, Pan P.; Madhavan, Raghavan; Peng, H. Benjamin

doi:10.1002/dvdy.23845

Cited by 6 publications

(5 citation statements)

References 118 publications

(101 reference statements)

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“…As expected, ROR1 transphosphorylation was induced by wild-type, full-length MET but not by the MET K1110A kinase-dead variant [21][22][23][24] (Fig. 1b).…”

Section: Met Domains Required For Ror1 Transphosphorylationsupporting

confidence: 83%

The ROR1 pseudokinase diversifies signaling outputs in MET‐addicted cancer cells

Gentile

Lazzari

Benvenuti

et al. 2014

Intl Journal of Cancer

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MET is a master gene controlling a genetic program driving proliferation, apoptosis protection and invasion. The ROR1 pseudokinase acts as a MET substrate. However, its contribution to MET signaling and MET-dependent biological outcomes remains to be elucidated. By structure-function analysis of ROR1 mutants, we show that ROR1 encompasses two major substrate regions: one is located in the proline-rich domain and is directly phosphorylated by MET; the other resides in the pseudokinase domain and is phosphorylated through intermediate activation of SRC. Differential phosphorylation of these two regions dictates the execution of specific responses: phosphorylation of the ROR1 proline-rich domain by MET-but not phosphorylation of the pseudokinase domain by SRC-is necessary and sufficient to control MET-driven proliferation and protection from apoptosis. Differently, both the proline-rich and the pseudokinase domains mediate cell invasion. Consistent with the role of ROR1 in specifying the functional consequences of MET-dependent signals, ROR1 silencing leads to selective attenuation of only some of the signal transduction pathways sustained by MET. These data enlighten the so far elusive function(s) of pseudokinases and identify a mechanism of biological diversification, based on substrate specificity of oncogenic kinases.Signals from receptor tyrosine kinases (RTKs) proceed through stereotyped pathways that can be tuned-and diversified-by surface coreceptors acting as adaptor substrates. This mode of information transfer is epitomized by the ERBB RTK network, which comprises four structurally homologous surface proteins (ERBB1-4). Within this family, some receptors (ERBB1, ERBB2 and ERBB4) are catalytically proficient enzymes that can autonomously trigger mitogenic cascades, whereas ERBB3 is a kinase defective receptor that acts only when associated with the other ERBB members. The formation of ERBB/ERBB3 heterodimers and the ensuing transphosphorylation of ERBB3 provide consensus sites for privileged activation of PI3K, which in turn encourages preferential execution of antiapoptotic responses. Another example of biochemical cross-talk between RTKs and companion substrates, which regulates quality and quantity of signaling outputs, is offered by the MET oncogene product. In this case, MET association with the a6b4 integrin results in tyrosine phosphorylation of the b4 cytoplasmic domain and the consequent SH2-mediated recruitment of a number of downstream transducers: Shc and PI3K add on analogous moieties directly associated with MET, thus providing a "mass effect" that sustains the strength and duration of RAS-dependent pathways and fosters cell proliferation 2,3 ; the Shp2 tyrosine phosphatase mainly mediates antiapoptotic effects via intermediate activation of SRC. 4 Recently, we identified the ROR1 protein as a novel partner of MET that undergoes transphosphorylation as a consequence of MET hyperactivation.5 In a functional screening of a panel of 43 cancer cell lines derived from various solid tumors, R...

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“…As expected, ROR1 transphosphorylation was induced by wild-type, full-length MET but not by the MET K1110A kinase-dead variant [21][22][23][24] (Fig. 1b).…”

Section: Met Domains Required For Ror1 Transphosphorylationsupporting

confidence: 83%

The ROR1 pseudokinase diversifies signaling outputs in MET‐addicted cancer cells

Gentile

Lazzari

Benvenuti

et al. 2014

Intl Journal of Cancer

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“…These co-receptors include fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor (HGFR) for both AAV2 and AAV3, platelet-derived growth factor receptor (PDGF) for AAV5, and epidermal growth factor receptor (EGFR) for AAV6 (Madigan and Asokan, 2016). Signaling through each of these receptors has been linked to NMJ formation/function (Zhao et al, 1999;Li et al, 2012;Taetzsch et al, 2018), consistent with their synaptic availability. Additional receptors have been identified for engineered serotypes contributing to distinct tropisms (Hordeaux et al, 2019;Huang et al, 2019).…”

Section: Adeno-associated Virusmentioning

confidence: 99%

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Tosolini

Sleigh

2020

Front. Mol. Neurosci.

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Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia. This route is minimally invasive and therefore clinically relevant for gene therapy targeting to peripheral nerve soma. For successful transgene expression, viruses administered into muscle must undergo a series of processes, including host cell interaction and internalization, intracellular sorting, long-range retrograde axonal transport, endosomal liberation, and nuclear import. In this review article, we outline key characteristics of major gene therapy viruses—adenovirus, adeno-associated virus (AAV), and lentivirus—and summarize the mechanisms regulating important steps in the virus journey from binding at peripheral nerve terminals to nuclear delivery. Additionally, we describe how neuropathology can negatively influence these pathways, and conclude by discussing opportunities to optimize the intramuscular administration route to maximize gene delivery and thus therapeutic potential.

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“…In normal development and tissue regeneration HGF/c-Met is crucial. HGF/c-Met has physiological roles in cardiovascular remodeling [ 50 ], skeletal muscle regeneration [ 51 ], differentiation and migration during spermatogenesis [ 52 ], axonal growth [ 53 ], renal tubulogenesis [ 54 ], and blood cell growth and differentiation [ 55 ]. Recently, HGF has been found to be elevated during cerebral aneurism promoting healing of tissue damage, and promotes organ regeneration.…”

Section: Role Of Hgf/c-met Signaling In Homeostasismentioning

confidence: 99%

Activated HGF-c-Met Axis in Head and Neck Cancer

Arnold

Enders

Thomas

2017

Cancers

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Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent’s pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal–epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes.

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Differential regulation of axonal growth and neuromuscular junction assembly by HGF/c‐Met signaling

Cited by 6 publications

References 118 publications

The ROR1 pseudokinase diversifies signaling outputs in MET‐addicted cancer cells

The ROR1 pseudokinase diversifies signaling outputs in MET‐addicted cancer cells

Intramuscular Delivery of Gene Therapy for Targeting the Nervous System

Activated HGF-c-Met Axis in Head and Neck Cancer

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