A role for the tyrosine kinase ACK1 in neurotrophin signaling and neuronal extension and branching

Abstract

Neurotrophins are involved in many crucial cellular functions, including neurite outgrowth, synapse formation, and plasticity. Although these events have long been known, the molecular determinants underlying neuritogenesis have not been fully characterized. Ack1 (activated Cdc42-associated tyrosine kinase) is a non-receptor tyrosine kinase that is highly expressed in the brain. Here, we demonstrate that Ack1 is a molecular constituent of neurotrophin signaling cascades in neurons and PC12 cells. We report that Ack1 interacts with Trk receptors and becomes tyrosine phosphorylated and its kinase activity is increased in response to neurotrophins. Moreover, our data indicate that Ack1 acts upstream of the Akt and MAPK pathways. We show that Ack1 overexpression induces neuritic outgrowth and promotes branching in neurotrophin-treated neuronal cells, whereas the expression of Ack1 dominant negatives or short-hairpin RNAs counteract neurotrophin-stimulated differentiation. Our results identify Ack1 as a novel regulator of neurotrophin-mediated events in primary neurons and in PC12 cells.

Whole-Exome Sequencing in Familial Parkinson Disease

“…Findings from some studies 31–33 suggest that TNK2 is involved in synaptic function and plasticity, and the results of a recent study 34 propose that TNK2 mutations may cause autosomal recessive infantile-onset epilepsy. Other studies 35,36 have established links between the TNK2 protein and the epidermal growth factor receptor ( EGFR [OMIM 131550]).…”

ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers

“… 20 The mechanistic details of ACK1 signaling in brain became recently available wherein in response to neurotrophins, ACK1 was shown to interact with Trk receptors leading to its activation, which in turn activated AKT. 21 Overall, these data indicate that ACK1 is an important player in neurotrophin signaling, neuronal extension and branching, however, the pathological significance of ACK1 signaling in brain was not entirely clear, till a Belgian-Italian family was identified where all the 3 siblings presented with autosomal recessive, infantile onset epilepsy and intellectual disability. 22 The exome sequencing identified a homozygous missense variant, V638M in the ACK1 ( Figure 1 ).…”

PDGFR‐β‐activated ACK1‐AKT Signaling Promotes Glioma Tumorigenesis

“…19 Phosphorylation at Y284 is required for ACK1 kinase activity, 17 and ACK1 is required for AKT activation. 15,[20][21][22] EGF stimulation activates ACK1, which in turn directly phosphorylates Y176 of AKT. 20 The robust activation of ACK1 can facilitate the development of prostatic intraepithelial neoplasias in mice and has been correlated with the survival outcome of breast cancer patients.…”