scholarly journals Rotational Coupling of the Transmembrane and Kinase Domains of the Neu Receptor Tyrosine Kinase

2000 ◽  
Vol 11 (10) ◽  
pp. 3589-3599 ◽  
Author(s):  
Charlotte A. Bell ◽  
John A. Tynan ◽  
Kristen C. Hart ◽  
April N. Meyer ◽  
Scott C. Robertson ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Receptor Dimerization ◽  
Activating Mutations ◽  
Rotational Coupling ◽  
Specific Orientation

Ligand binding to receptor tyrosine kinases (RTKs) regulates receptor dimerization and activation of the kinase domain. To examine the role of the transmembrane domain in regulation of RTK activation, we have exploited a simplified transmembrane motif, [VVVEVVV]n, previously shown to activate the Neu receptor. Here we demonstrate rotational linkage of the transmembrane domain with the kinase domain, as evidenced by a periodic activation of Neu as the dimerization motif is shifted across the transmembrane domain. These results indicate that activation requires a specific orientation of the kinase domains with respect to each other. Results obtained with platelet-derived growth factor receptor-β suggest that this rotational linkage of the transmembrane domain to the kinase domain may be a general feature of RTKs. These observations suggest that activating mutations in RTK transmembrane and juxtamembrane domains will be limited to those residues that position the kinase domains in an allowed rotational conformation.

scholarly journals Transmembrane Domain Sequence Requirements for Activation of the p185c-neu Receptor Tyrosine Kinase

1997 ◽  
Vol 137 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Lucinda I. Chen ◽  
Melanie K. Webster ◽  
April N. Meyer ◽  
Daniel J. Donoghue
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tandem Repeats ◽  
Transmembrane Domain ◽  
Recent Observation ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Transmembrane Domains ◽  
Activating Mutations ◽  
Sequence Requirements

The receptor tyrosine kinase p185c-neu can be constitutively activated by the transmembrane domain mutation Val664→ Glu, found in the oncogenic mutant p185neu. This mutation is predicted to allow intermolecular hydrogen bonding and receptor dimerization. Understanding the activation of p185c-neu has assumed greater relevance with the recent observation that achondroplasia, the most common genetic form of human dwarfism, is caused by a similar transmembrane domain mutation that activates fibroblast growth factor receptor (FGFR) 3. We have isolated novel transforming derivatives of p185c-neu using a large pool of degenerate oligonucleotides encoding variants of the transmembrane domain. Several of the transforming isolates identified were unusual in that they lacked a Glu at residue 664, and others were unique in that they contained multiple Glu residues within the transmembrane domain. The Glu residues in the transforming isolates often exhibited a spacing of seven residues or occurred in positions likely to represent the helical interface. However, the distinction between the sequences of the transforming clones and the nontransforming clones did not suggest clear rules for predicting which specific sequences would result in receptor activation and transformation. To investigate these requirements further, entirely novel transmembrane sequences were constructed based on tandem repeats of simple heptad sequences. Activation was achieved by transmembrane sequences such as [VVVEVVA]n or [VVVEVVV]n, whereas activation was not achieved by a transmembrane domain consisting only of Val residues. In the context of these transmembrane domains, Glu or Gln were equally activating, while Lys, Ser, and Asp were not. Using transmembrane domains with two Glu residues, the spacing between these was systematically varied from two to eight residues, with only the heptad spacing resulting in receptor activation. These results are discussed in the context of activating mutations in the transmembrane domain of FGFR3 that are responsible for the human developmental syndromes achondroplasia and acanthosis nigricans with Crouzon Syndrome.

Platelet-derived growth factor receptor alpha (PDGFRA) and C-Kit immunohistochemistry (IHC) in gastrointestinal stromal tumours (GISTs)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15156-15156
Author(s):  
D. Skarlos ◽  
E. Kyrodimou ◽  
N. Papakonstantinou ◽  
G. Klouvas ◽  
C. Christodoulou ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Gastrointestinal Stromal Tumours ◽  
Exact Role ◽  
Male Predominance ◽  
Activating Mutations ◽  
Study Materials ◽  
Factor Receptor Alpha

15156 Background: The vast majority of GISTs show activating mutations of the genes coding for c-kit (CD 117) and PDGFRA, two receptor tyrosine kinases (RTKs). The exact role of PDGFRA as this expressed immunohistochemically (IHC), has not been fully elucidated in the diagnosis and treatment of GISTs. The aim of this study was (1) to try to correlate the pathological features of patients (pts) with GISTs, with c-kit and PDGFRA as these expressed by IHC and 2) to correlate the c-kit and PDGFRA with the clinical outcome of the pts. We report here the first part of the study. Materials and Methods: Twenty one (21) pts with GISTs were studied 14 located in the stomach, 3 in small bowel, 3 in colon and 1 in the mesenterium. Criteria for positivity of c-kit were strong membranus, cytoplasmic and paranuclear staining and for PDGFRA dot-like or Golgi pattern of staining. Median age was 61 years while there was a male predominance. Results: C-kit was detected in 95% of cases while PDGFRA in 90.5%. All the GISTs that were positive for PDGFRA were also positive for c-kit. Conclusions: Preliminary results of the first part of the study show that an accurate diagnosis of GISTs can be achieved based on the conventional histological and IHC criteria without the need for mutational analysis. No significant financial relationships to disclose.

scholarly journals Syndecan Transmembrane Domain Specifically Regulates Downstream Signaling Events of the Transmembrane Receptor Cytoplasmic Domain

2021 ◽  
Vol 22 (15) ◽  
pp. 7918
Author(s):  
Jisun Hwang ◽  
Bohee Jang ◽  
Ayoung Kim ◽  
Yejin Lee ◽  
Joonha Lee ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Cytoplasmic Domain ◽  
Nih3t3 Cells ◽  
C Elegans ◽  
Downstream Signaling ◽  
Downstream Effectors ◽  
Signaling Events

Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.

scholarly journals Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1690
Author(s):  
Louise Pinet ◽  
Nadine Assrir ◽  
Carine van Heijenoort
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Domain ◽  
Cellular Motility ◽  
Dynamic Features ◽  
Sh2 Domains ◽  
Intrinsically Disordered ◽  
Src Homology ◽  
Regulation Functions ◽  
And Function

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features.

scholarly journals Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.

1993 ◽  
Vol 13 (11) ◽  
pp. 6711-6722 ◽  
Author(s):  
G A Rodrigues ◽  
M Park
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Leucine Zipper ◽  
Kinase Domain ◽  
Site Directed Mutagenesis ◽  
Leucine Zipper Motif ◽  
Transforming Activity ◽  
Met Oncogene ◽  
Hepatocyte Growth

Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.

Distribution and pathogenicity of nsSNPs in receptor tyrosine kinases (RTKs) in patients with colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15012-e15012
Author(s):  
Matthew K Stein ◽  
Saradasri Karri ◽  
Lindsay Kaye Morris ◽  
Srishti Sareen ◽  
Kruti Patel ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tyrosine Kinases ◽  
Transmembrane Domain ◽  
Hot Spot ◽  
In Silico Analysis ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Nucleotide Polymorphisms ◽  
Significant Difference ◽  
Carboxy Terminal

e15012 Background: Non-synonymous single nucleotide polymorphisms (nsSNPs) occur along the entire sequence of RTKs and can promote oncogenic activity. As prior “hot-spot” testing was limited to the tyrosine kinase domain (TKD), next-generation sequencing (NGS) allows the discovery of novel extra-TKD variants. Methods: We analyzed all nsSNPs in 29 RTKs of colon cancer patients (pts) who received tumor profiling (2013-2015) with Caris NGS. Mutations were classified by location including the TKD, extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM) and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to predict if damaging (pnsSNP). Results: 110 pts were identified with a median age of 58 years (range 37-86); 55% male; 57% white, 41% black. 51 were KRAS+, 12 BRAF+, 5 NRAS+ and 5 were microsatellite unstable (MSI-H); 67 were left-sided, 31 right-sided, 10 transverse and 2 unknown. A total of 171 nsSNPs and 7 pathogenic mutations (Pmut) were detected: ERBB2 (ECD S310F, TKD V777L and TKD V842I), ERBB3 (ECD A232V and TKD Q809R), FGFR2 (ECD S252L) and RET (TKD L790F). 83/110 (76%) pts had ≥1 RTK mutation (median 1; range 0-9). 72/171 (42%) variants were pnsSNPs and found in 50 (45%) pts; 14% of pts had ≥2. All 29 RTKs had nsSNPs with median 6 (range 2-12); 24/29 RTKs had a Pmut or pnsSNP (median 2; range 0-8). RTKs with the most nsSNPs were EPHA5 (8/10 were pnsSNPs), PDGFA (7/8), ALK (6/8), ERBB4 (5/8), NTRK3 (5/6), cKIT (4/9), ROS1 (3/12), PDGFRB (3/6) and FGFR1 (3/6). nsSNPs were distributed across all RTK domains: 50% were ECD (30/86 pnsSNPs), 27% TKD (28/46), 13% CT (7/22), 5% JM (6/9) and 5% TM (1/8). No significant difference was seen between pnsSNP incidence and sidedness or KRAS/BRAF/NRAS status. In MSI-H pts, 13/22 variants were pnsSNPs (median 2; 1-5); 4/5 MSI-H were right-sided (Fisher’s exact p < 0.01). Conclusions: > 70% colon cancer pts had ≥1 mutation in 29 RTKs with > 70% outside the TKD, and > 40% pnsSNPs. MSI-H had a higher incidence of pnsSNPs; further study is warranted to determine their significance and actionability.

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1931-1939 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Growth Factor Receptor ◽  
Myeloproliferative Disorders ◽  
Hematologic Malignancies ◽  
Myeloid Metaplasia ◽  
Activating Mutations ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

scholarly journals Gastrointestinal Stromal Tumor: Advances in Diagnosis and Management

2011 ◽  
Vol 135 (10) ◽  
pp. 1298-1310 ◽  
Author(s):  
Deepa T Patil ◽  
Brian P Rubin
Keyword(s):  
Gastrointestinal Tract ◽  
Tyrosine Kinases ◽  
English Literature ◽  
Cleveland Clinic ◽  
Growth Factor Receptor ◽  
Mesenchymal Tumors ◽  
Sunitinib Malate ◽  
Activating Mutations ◽  
Mesenchymal Neoplasms ◽  
Pharmacologic Inhibitors

Context.—Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and should be differentiated from other mesenchymal tumors. They harbor specific activating mutations in the KIT or platelet-derived growth factor receptor α (PDGFRA) receptor tyrosine kinases, which makes them responsive to pharmacologic inhibitors, such as imatinib mesylate and sunitinib malate. Objectives.—To provide a comprehensive review of the pathogenesis of GIST and the underlying principles of targeted therapy, to review the salient histologic and immunohistochemical features that facilitate the distinction of GIST from other mesenchymal neoplasms of the gastrointestinal tract, and to present the prognostic parameters for risk stratification that guide clinical management. Data Sources.—Review of the English literature through PubMed as well as personal experience. Photographs were taken from cases encountered at the Cleveland Clinic. Conclusions.—The discovery of the KIT-GIST connection has not only improved the diagnostic accuracy of GISTs but also provided us with a better understanding of the histogenesis and molecular pathogenesis of these neoplasms.

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