scholarly journals Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation

2021 ◽  
Vol 118 (33) ◽  
pp. e2101496118
Author(s):  
Linda Truebestein ◽  
Harald Hornegger ◽  
Dorothea Anrather ◽  
Markus Hartl ◽  
Kaelin D. Fleming ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Growth Factor ◽  
Protein Kinase ◽  
Second Messengers ◽  
Kinase Domain ◽  
Activation Loop ◽  
Growth Factor Signaling ◽  
Ph Domain ◽  
Protein Kinase Akt ◽  
Spatiotemporal Control

The protein kinase Akt is one of the primary effectors of growth factor signaling in the cell. Akt responds specifically to the lipid second messengers phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] via its PH domain, leading to phosphorylation of its activation loop and the hydrophobic motif of its kinase domain, which are critical for activity. We have now determined the crystal structure of Akt1, revealing an autoinhibitory interface between the PH and kinase domains that is often mutated in cancer and overgrowth disorders. This interface persists even after stoichiometric phosphorylation, thereby restricting maximum Akt activity to PI(3,4,5)P3- or PI(3,4)P2-containing membranes. Our work helps to resolve the roles of lipids and phosphorylation in the activation of Akt and has wide implications for the spatiotemporal control of Akt and potentially lipid-activated kinase signaling in general.

scholarly journals Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis

Structure ◽  
1999 ◽  
Vol 7 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Michele A McTigue ◽  
John A Wickersham ◽  
Chris Pinko ◽  
Richard E Showalter ◽  
Camran V Parast ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Vascular Endothelial ◽  
Key Enzyme ◽  
Endothelial Growth Factor

scholarly journals Structural pathway for allosteric activation of the autophagic PI 3-kinase complex I

2019 ◽  
Vol 116 (43) ◽  
pp. 21508-21513 ◽  
Author(s):  
Lindsey N. Young ◽  
Felix Goerdeler ◽  
James H. Hurley
Keyword(s):  
Protein Kinase ◽  
Complex I ◽  
Structural Changes ◽  
Kinase Domain ◽  
Activation Loop ◽  
Class Iii ◽  
Lipid Kinase ◽  
Protein Kinase Domain ◽  
Autophagy Induction ◽  
Enzymatic Activation

Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the proautophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryoelectron microscopy was used to visualize a 2-step PI3KC3-C1 activation pathway driven by NRFB2 MIT domain binding. Binding of a single NRBF2 MIT domain bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes.

scholarly journals A crystal structure of the human protein kinase Mps1 reveals an ordered conformation of the activation loop

2019 ◽  
Vol 87 (4) ◽  
pp. 348-352
Author(s):  
Jacomina C. Roorda ◽  
Robbie P. Joosten ◽  
Anastassis Perrakis ◽  
Yoshitaka Hiruma
Keyword(s):  
Crystal Structure ◽  
Protein Kinase ◽  
Human Protein ◽  
Activation Loop ◽  
Human Protein Kinase

scholarly journals Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor

2010 ◽  
Vol 189 (5) ◽  
pp. 871-883 ◽  
Author(s):  
Lai Kuan Goh ◽  
Fangtian Huang ◽  
Woong Kim ◽  
Steven Gygi ◽  
Alexander Sorkin
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Kinase Domain ◽  
Mitogen Activated Protein Kinase ◽  
Epidermal Growth ◽  
Egfr Mutant

Endocytosis of the epidermal growth factor receptor (EGFR) is important for the regulation of EGFR signaling. However, EGFR endocytosis mechanisms are poorly understood, which precludes development of approaches to specifically inhibit EGFR endocytosis and analyze its impact on signaling. Using a combination of receptor mutagenesis and RNA interference, we demonstrate that clathrin-dependent internalization of activated EGFR is regulated by four mechanisms, which function in a redundant and cooperative fashion. These mechanisms involve ubiquitination of the receptor kinase domain, the clathrin adaptor complex AP-2, the Grb2 adaptor protein, and three C-terminal lysine residues (K1155, K1158, and K1164), which are acetylated, a novel posttranslational modification for the EGFR. Based on these findings, the first internalization-defective EGFR mutant with functional kinase and normal tyrosine phosphorylation was generated. Analysis of the signaling kinetics of this mutant revealed that EGFR internalization is required for the sustained activation of protein kinase B/AKT but not for the activation of mitogen-activated protein kinase.

scholarly journals The Crystal Structure of the Active Form of the C-Terminal Kinase Domain of Mitogen- and Stress-Activated Protein Kinase 1

2010 ◽  
Vol 399 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Margarita Malakhova ◽  
Igor D'Angelo ◽  
Hong-Gyum Kim ◽  
Igor Kurinov ◽  
Ann M. Bode ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Protein Kinase ◽  
Active Form ◽  
Kinase Domain

scholarly journals Erratum: Corrigendum: Protein kinase CK2 links extracellular growth factor signaling with the control of p27Kip1 stability in the heart

2008 ◽  
Vol 14 (5) ◽  
pp. 585-585 ◽  
Author(s):  
Ludger Hauck ◽  
Christoph Harms ◽  
Junfeng An ◽  
Jens Rohne ◽  
Karen Gertz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Protein Kinase Ck2 ◽  
Growth Factor Signaling ◽  
Kinase Ck2

scholarly journals Momelotinib is a highly potent inhibitor of FLT3-mutant AML

2021 ◽  
Author(s):  
Mohammad Azhar ◽  
Zachary Kincaid ◽  
Meenu Kesarwani ◽  
Tahir Latif ◽  
Daniel Starczynowski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Initial Response ◽  
Leukemic Cells ◽  
Activation Loop ◽  
Growth Factor Signaling ◽  
Durable Response ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors

Kinase activating mutation in FLT3 is the most frequent genetic lesion associated with poor prognosis in acute myeloid leukemia (AML). Therapeutic response to FLT3 tyrosine kinase inhibitor (TKI) therapy is dismal, and many patients relapse even after allogeneic stem cell transplantation. Despite the introduction of more selective FLT3 inhibitors, remissions are short-lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are two principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to more profound and lasting clinical responses. Here we show that the JAK2 inhibitor, momelotinib, is an equipotent type-1 FLT3 inhibitor. Momelotinib showed potent inhibitory activity on both mouse and human cells expressing FLT3-ITD, including clinically relevant resistant mutations within the activation loop at residues D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by FLT3 ligand (FL), and hematopoietic cytokine activated JAK2 signaling. Interestingly, unlike gilteritinib, momelotinib inhibits the expression of MYC in leukemic cells. Consequently, concomitant inhibition of FLT3 and downregulation of MYC by momelotinib treatment showed better efficacy in suppressing the leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.

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