Search results for: Titus J. Boggon

Items from 1 to 20 out of 37 results

article

The pseudoGTPase group of pseudoenzymes

Amy L. Stiegler, Titus J. Boggon

The FEBS Journal > 287 > 19 > 4232 - 4245

Pseudoenzymes are emerging as significant mediators and regulators of signal transduction. These proteins maintain enzyme folds and topologies, but are disrupted in the conserved motifs required for enzymatic activity. Among the pseudoenzymes, the pseudoGTPase group of atypical GTPases has recently expanded and includes the Rnd and RGK groups, RhoH and the RhoBTB proteins, mitochondrial RhoGTPase...

article

MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation

Lingtao Jin, Jaemoo Chun, Chaoyun Pan, Dan Li, more

Cancer Cell > 2018 > 34 > 2 > 315-330.e7

Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while...

article

PAK4 crystal structures suggest unusual kinase conformational movements

Eric Y. Zhang, Byung Hak Ha, Titus J. Boggon

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics > 2018 > 1866 > 2 > 356-365

In order for protein kinases to exchange nucleotide they must open and close their catalytic cleft. These motions are associated with rotations of the N-lobe, predominantly around the ‘hinge region’. We conducted an analysis of 28 crystal structures of the serine-threonine kinase, p21-activated kinase 4 (PAK4), including three newly determined structures in complex with staurosporine, FRAX486, and...

article

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, more

Molecular Cell > 2016 > 64 > 5 > 859-874

Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers,...

article

Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension

Sílvia Vilarinho, Sinan Sari, Güldal Yilmaz, Amy L. Stiegler, more

Hepatology > 63 > 6 > 1977 - 1986

Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early‐onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate...

article

Structural Basis for Noncanonical Substrate Recognition of Cofilin/ADF Proteins by LIM Kinases

Stephanie Hamill, Hua Jane Lou, Benjamin E. Turk, Titus J. Boggon

Molecular Cell > 2016 > 62 > 3 > 397-408

Cofilin/actin-depolymerizing factor (ADF) proteins are critical nodes that relay signals from protein kinase cascades to the actin cytoskeleton, in particular through site-specific phosphorylation at residue Ser3. This is important for regulation of the roles of cofilin in severing and stabilizing actin filaments. Consequently, cofilin/ADF Ser3 phosphorylation is tightly controlled as an almost exclusive...

article

Structural analysis of the KRIT1 ankyrin repeat and FERM domains reveals a conformationally stable ARD–FERM interface

Rong Zhang, Xiaofeng Li, Titus J. Boggon

Journal of Structural Biology > 2015 > 192 > 3 > 449-456

Cerebral cavernous malformations (CCM) are vascular dysplasias that usually occur in the brain and are associated with mutations in the KRIT1/CCM1, CCM2/MGC4607/OSM/Malcavernin, and PDCD10/CCM3/TFAR15 genes. Here we report the 2.9Å crystal structure of the ankyrin repeat domain (ARD) and FERM domain of the protein product of KRIT1 (KRIT1; Krev interaction trapped 1). The crystal structure reveals...

article

Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling

Hee-Bum Kang, Jun Fan, Ruiting Lin, Shannon Elf, more

Molecular Cell > 2015 > 59 > 3 > 345-358

Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Here we demonstrate a “synthetic lethal” interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing...

article

Structure of the ABL2/ARG kinase in complex with dasatinib

Byung Hak Ha, Mark Adam Simpson, Anthony J. Koleske, Titus J. Boggon

Acta Crystallographica Section F > 71 > 4 > 443 - 448

ABL2/ARG (ABL‐related gene) belongs to the ABL (Abelson tyrosine‐protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts...

article

Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

Lingtao Jin, Dan Li, Gina N. Alesi, Jun Fan, more

Cancer Cell > 2015 > 27 > 2 > 257-270

How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically,...

article

The Strength and Cooperativity of KIT Ectodomain Contacts Determine Normal Ligand-Dependent Stimulation or Oncogenic Activation in Cancer

Andrey V. Reshetnyak, Yarden Opatowsky, Titus J. Boggon, Ewa Folta-Stogniew, more

Molecular Cell > 2015 > 57 > 1 > 191-201

The receptor tyrosine kinase KIT plays an important role in development of germ cells, hematopoietic cells, and interstitial pacemaker cells. Oncogenic KIT mutations play an important “driver” role in gastrointestinal stromal tumors, acute myeloid leukemias, and melanoma, among other cancers. Here we describe the crystal structure of a recurring somatic oncogenic mutation located in the C-terminal...

article

Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

Changliang Shan, Shannon Elf, Quanjiang Ji, Hee-Bum Kang, more

Molecular Cell > 2014 > 55 > 4 > 552-565

Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP ⁺ binding to 6PGD and formation of active 6PGD...

article

Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex

Jun Fan, Changliang Shan, Hee-Bum Kang, Shannon Elf, more

Molecular Cell > 2014 > 53 > 4 > 534-548

Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal...

article

Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors

Jaehyuk Choi, Sean F. Landrette, Tiffany Wang, Perry Evans, more

Pigment Cell & Melanoma Research > 27 > 2 > 253 - 262

BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole‐exome sequencing of drug‐resistant BRAF^V600K melanoma cells. We further describe a new screening approach, a genome‐wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N‐terminal BRAF...

article

Identification of a Major Determinant for Serine-Threonine Kinase Phosphoacceptor Specificity

Catherine Chen, Byung Hak Ha, Anastasia F. Thévenin, Hua Jane Lou, more

Molecular Cell > 2014 > 53 > 1 > 140-147

Eukaryotic protein kinases are generally classified as being either tyrosine or serine-threonine specific. Though not evident from inspection of their primary sequences, many serine-threonine kinases display a significant preference for serine or threonine as the phosphoacceptor residue. Here we show that a residue located in the kinase activation segment, which we term the “DFG+1” residue, acts as...

article

Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

Oriana S. Fisher, Titus J. Boggon

Cellular and Molecular Life Sciences > 2014 > 71 > 10 > 1881-1892

Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM),...

article

Mineralocorticoid Receptor Phosphorylation Regulates Ligand Binding and Renal Response to Volume Depletion and Hyperkalemia

Shigeru Shibata, Jesse Rinehart, Junhui Zhang, Gilbert Moeckel, more

Cell Metabolism > 2013 > 18 > 5 > 660-671

Nuclear receptors are transcription factors that regulate diverse cellular processes. In canonical activation, ligand availability is sufficient to produce receptor binding, entraining downstream signaling. The mineralocorticoid receptor (MR) is normally activated by aldosterone, which is produced in both volume depletion and hyperkalemia, states that require different homeostatic responses. We report...

article

A Network of Interactions Enables CCM3 and STK24 to Coordinate UNC13D-Driven Vesicle Exocytosis in Neutrophils

Yong Zhang, Wenwen Tang, Haifeng Zhang, Xiaofeng Niu, more

Developmental Cell > 2013 > 27 > 2 > 215-226

Neutrophil degranulation plays an important role in acute innate immune responses and is tightly regulated because the granule contents can cause tissue damage. However, this regulation remains poorly understood. Here, we identify the complex of STK24 and CCM3 as being an important regulator of neutrophil degranulation. Lack of either STK24 or CCM3 increases the release of a specific granule pool...

article

MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL

Kathryn A. Tworkoski, James T. Platt, Antonella Bacchiocchi, Marcus Bosenberg, more

Pigment Cell & Melanoma Research > 26 > 4 > 527 - 541

The receptor tyrosine kinase AXL regulates melanoma cell proliferation and migration. We now demonstrate that AXL and the related kinase MERTK are alternately expressed in melanoma and are associated with different transcriptional signatures. MERTK‐positive melanoma cells are more proliferative and less migratory than AXL‐positive melanoma cells and overexpression of AXL increases cell motility relative...

article

Cocrystal structure of the ICAP1 PTB domain in complex with a KRIT1 peptide

Weizhi Liu, Titus J. Boggon

Acta Crystallographica Section F > 69 > 5 > 494 - 498

Integrin cytoplasmic domain‐associated protein‐1 (ICAP1) is a suppressor of integrin activation and directly binds to the cytoplasmic tail of β1 integrins; its binding suppresses integrin activation by competition with talin. Krev/Rap1 interaction trapped‐1 (KRIT1) releases ICAP1 suppression of integrin activation by sequestering ICAP1 away from integrin cytoplasmic tails. Here, the cocrystal structure...

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Search results for: Titus J. Boggon

The pseudoGTPase group of pseudoenzymes

MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation

PAK4 crystal structures suggest unusual kinase conformational movements

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension

Structural Basis for Noncanonical Substrate Recognition of Cofilin/ADF Proteins by LIM Kinases

Structural analysis of the KRIT1 ankyrin repeat and FERM domains reveals a conformationally stable ARD–FERM interface

Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling

Structure of the ABL2/ARG kinase in complex with dasatinib

Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

The Strength and Cooperativity of KIT Ectodomain Contacts Determine Normal Ligand-Dependent Stimulation or Oncogenic Activation in Cancer

Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

Tyr Phosphorylation of PDP1 Toggles Recruitment between ACAT1 and SIRT3 to Regulate the Pyruvate Dehydrogenase Complex

Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors

Identification of a Major Determinant for Serine-Threonine Kinase Phosphoacceptor Specificity

Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

Mineralocorticoid Receptor Phosphorylation Regulates Ligand Binding and Renal Response to Volume Depletion and Hyperkalemia

A Network of Interactions Enables CCM3 and STK24 to Coordinate UNC13D-Driven Vesicle Exocytosis in Neutrophils

MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL

Cocrystal structure of the ICAP1 PTB domain in complex with a KRIT1 peptide

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