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ALK tyrosine kinase receptor

Definition:

Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response. In contrast, ALKAL1 is not a potent physiological ligand for ALK. Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK). PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.

References:

[1]. Steven De Munck, et al. Structural basis of cytokine-mediated activation of ALK family receptors. Nature. 2021 Dec;600(7887):143-147. [Content Brief]

[2]. Akira Motegi, et al. ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth. J Cell Sci. 2004 Jul 1;117(Pt 15):3319-29. [Content Brief]

[3]. Andrey V Reshetnyak, et al. Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature. 2021 Dec;600(7887):153-157. [Content Brief]

[4]. Marcus Borenäs, et al. ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. EMBO J. 2021 Feb 1;40(3):e105784. [Content Brief]

[5]. Emma T Bowden, et al. Anti-apoptotic signaling of pleiotrophin through its receptor, anaplastic lymphoma kinase. J Biol Chem. 2002 Sep 27;277(39):35862-8. [Content Brief]

[6]. G E Stoica, et al. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 2001 May 18;276(20):16772-9. [Content Brief]

[7]. Ciaran Powers, et al. Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. J Biol Chem. 2002 Apr 19;277(16):14153-8. [Content Brief]

[8]. Gerald E Stoica, et al. Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 2002 Sep 27;277(39):35990-8. [Content Brief]

[9]. Andrey V Reshetnyak, et al. Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α). Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):8340-8345. [Content Brief]

[10]. Jean Y Gouzi, et al. Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells. J Cell Sci. 2005 Dec 15;118(Pt 24):5811-23. [Content Brief]

[11]. Joffrey Degoutin, et al. ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation. FEBS Lett. 2007 Feb 20;581(4):727-34. [Content Brief]

[12]. I Simonitsch, et al. The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation. FASEB J. 2001 Jun;15(8):1416-8. [Content Brief]

[13]. A H Kuo, et al. Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene. 2007 Feb 8;26(6):859-69. [Content Brief]

[14]. B Souttou, et al. Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. J Biol Chem. 2001 Mar 23;276(12):9526-31. [Content Brief]

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