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.

Distribution and pathogenicity of nsSNPs in receptor tyrosine kinases (RTKs) in non-small cell lung cancer (NSCLC) patients (pts).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20618-e20618
Author(s):  
Ari M. Vanderwalde ◽  
Matthew K Stein ◽  
Lindsay Kaye Morris ◽  
Srishti Sareen ◽  
Saradasri Karri ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinases ◽  
In Silico ◽  
Transmembrane Domain ◽  
Stage Iv ◽  
In Silico Analysis ◽  
Large Cell ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Silico Analysis

e20618 Background: Non-synonymous SNPs (nsSNPs) in RTKs can alter kinase activity and are not exclusive to the tyrosine kinase domain (TKD). In NSCLC, EGFR lesions were previously identified using TKD-limited tests; however, next-generation sequencing (NGS) enables the entire protein sequence of many RTKs to be interrogated. Methods: We analyzed all nsSNPs in 28 RTKs in lung cancer pts who received tumor profiling with Caris NGS from 2013-2015. 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 pathogenicity. Results: 167 pts (156 NSCLC, 11 SC) were identified with a median age 65 (range 26-85); 51% male; 65% white, 31% black; 77% ≥20 pack-years (py), 11% non-smokers; 52% samples tested were metastases. NSCLC pts were 63% adenocarcinoma, 22%, squamous, 8% large-cell; 81% stage IV, 14% III; 17 were EGFR+, 6 BRAF+, 3 HER2+, 3 ROS1 rearranged and 1 MET exon 14. A total 300 nsSNPs (286 NSCLC, 14 SC) were found in 28 RTKs, excluding EGFR. 123/156 NSCLC pts (79%) and 9/11 SC (82%) had ≥1 RTK lesion with median 2 (range 0-8); 143/300 (48%) nsSNPs were predicted-damaging (pnsSNP) by in silico and 89 pts (53%) had ≥1 pnsSNP (median 1; range 0-5). 28/28 RTKs had ≥3 mutations, with median 11 (range 3-23), and 26/28 contained ≥1 pnsSNP (median 5; range 0-14). RTKs in NSCLC with the most frequent nsSNPs were EPHA3 (14/23 variants were pnsSNP), EPHA5 (11/17), EPHB1 (10/11), RET (9/11), ERBB4 (8/12), ALK (7/16), NTRK3 (7/15), ROS1 (6/22) and FLT1 (6/15). 6/14 lesions in SC pts were pnsSNPs in ERBB3, ERBB4, FGFR1, FLT1, RET and ROS1. nsSNPs were found along RTKs: 57% were ECD (72/172 pnsSNP), 26% TKD (47/77), 10% CT (14/29), 6% JM (8/18) and 1% TM (2/4). 6/6 SC pnsSNPs were ECD. 67% BRAF+ and ROS1-rearranged, 59% EGFR+, 33% HER2+ and 0/1 MET exon 14 pts had ≥1 pnsSNP. Conclusions: Nearly 80% NSCLC and SC pts had ≥1 nsSNP in 28 RTKs, excluding EGFR, with 48% pnsSNPs by in silico analysis. As > 70% nsSNPs were extra-TKD lesions, further characterization is needed to identify kinase-effecting variants and their potential clinical significance.

Distribution of receptor tyrosine kinase (RTK) nsSNPs in breast cancer (BC) patients (pts) using next-generation sequencing (NGS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1080-1080
Author(s):  
Lindsay Kaye Morris ◽  
Matthew Stein ◽  
Saradasri Karri ◽  
Srishti Sareen ◽  
Kruti Patel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Triple Negative ◽  
Transmembrane Domain ◽  
In Silico Analysis ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Oncogenic Signaling ◽  
Frequent Mutations ◽  
Carboxy Terminal ◽  
Next Generation Sequencing Ngs

1080 Background: Non-synonymous SNPs (nsSNPs) discovered by NGS occurring in RTKs’ conserved topology in pts with BC may promote oncogenic signaling and hence may be actionable. Methods: We analyzed BC pts for nsSNPs in 29 RTKs identified by tumor profiling with NGS from Caris during 2013-2015. Mutations were classified by location including the tyrosine kinase domain (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 determine pathogenicity. Results: 79 pts were identified with a median age of 58 years (range 32-83); 99% female; 60% white, 38% black and 2% other. 77 pts were classifiable with 8 (10%) triple-positive, 35 (46%) ER+/PR+/HER2- (ER/PR+), 10 (13%) ER-/PR-/HER2+ (HER2+) and 24 (31%) triple-negative. 78 nsSNPs and 1 Caris-reported pathogenic substitution of ERBB3 (TKD S846I) were found. 52/79 (66%) pts had ≥1 RTK nsSNP (range 0-4); 28/29 RTKs had ≥1 nsSNP with median of 2 (range 0-15). In 28 pts (35%), 40% of nsSNPs were predicted to be damaging (pnsSNP) and 3 pts had 2 pnsSNPs. 17/29 RTKs had pnsSNPs, median 1 (range 0-9). The most commonly mutated RTKs were ROS1 (9/15 variants were pnsSNPs), ALK (3/4), EPHA5 (3/3), FLT4 (2/5), cKIT (2/4) and ERBB4 (2/3). ROS1 and ALK nsSNPs were most-frequently seen in ER/PR+ (9/15 pnsSNPs), triple-positive (3/3) and HER2+ (0/2) pts; no triple-negative pts had such variants. 100% triple-positive pts (6/8 pnsSNP), 69% ER/PR+ (18/35), 60% HER2+ (2/10) and 58% triple-negative (3/24) had RTK nsSNP. nsSNP were spread in all 5 RTK regions: 58% localized to the ECD (20/45 pnsSNPs), 17% TKD (8/13), 9% CT (2/7), 9% TM (1/7) and 8% JM (1/6) lesions were found. Of 9 ROS1 pnsSNPs, 7 were ECD, 1 CT and 1 TKD. Conclusions: 35% of BC pts had pnsSNP in RTKs across various phenotypes including frequent mutations in potentially actionable genes such as ROS1 and ALK. 26% of ER/PR+ pts had pnsSNPs in ROS1 or ALK. nsSNPs in the ECD or TKD were most likely to be damaging.

Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain (TKD) with next-generation sequencing (NGS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20506-e20506
Author(s):  
Matthew K Stein ◽  
Lindsay Kaye Morris ◽  
Jennifer Sullivan ◽  
Moon Jung Fenton ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Stage Iv ◽  
In Silico Analysis ◽  
Large Cell ◽  
Kinase Domain ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Carboxy Terminal

e20506 Background: While conventional organization of EGFR mutations in NSCLC includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to TKD in exons 18-21, NGS raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. Methods: Patients (pts) with lung cancer who received tumor profiling with NGS from 2013-2015 via Caris were identified. EGFR mutations were arranged based upon their known distribution relative to the TKD. In silico analysis was performed with PolyPhen-2 (Harvard) to predict nsSNPs’ pathogenicity. Results: 259 pts (248 NSCLC, 11 SC) had median age 65 years (26-85); 50% female; 64% white, 34% black; 73% with ≥20 pack-years (py), 12% non-smokers; 53% of samples were metastases. 65% NSCLC were adenocarcinoma (A), 21% squamous (S), 8% large-cell; 87% stage IV, 12% III. 44 EGFR variants were seen in 40 pts (15%; 39 NSCLC, 1 SC). While 32 pts had TKD lesions demonstrable through standard testing, 8 had extra-TKD mutations (8/44), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 2 carboxy terminal (CT). Aside from pathogenic ECD mutation G598V, 5/7 extra-TKD nsSNPs were predicted-damaging (pnsSNP) with in silico (Table 1). 7/7 extra-TKD nsSNP+ pts smoked (6/7 ≥20 py) and all 6 NSCLC pts were stage IV; 50% A, 17% S; 83% male. The pt with JM R675Q had erlotinib, 150 mg daily, added following progression of stage IV NSCLC on carboplatin and paclitaxel and had a partial response for 4 months. No other pt received EGFR-directed therapy. Conclusions: 2% NSCLC cases in our cohort had EGFR pnsSNPs located outside of the TKD, representing >18% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets. [Table: see text]

Functional dissection of p56lck, a protein tyrosine kinase which mediates interleukin-2-induced activation of the c-fos gene

1994 ◽  
Vol 14 (9) ◽  
pp. 5812-5819
Author(s):  
H Shibuya ◽  
K Kohu ◽  
K Yamada ◽  
E L Barsoumian ◽  
R M Perlmutter ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Gene Activation ◽  
Interleukin 2 ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Amino Acid Residues ◽  
Protein Tyrosine ◽  
Responsive Element

Members of the newly identified receptor family for cytokines characteristically lack the intrinsic protein tyrosine kinase domain that is a hallmark of other growth factor receptors. Instead, accumulating evidence suggests that these receptors utilize nonreceptor-type protein tyrosine kinases for downstream signal transduction by cytokines. We have shown previously that the interleukin-2 receptor beta-chain interacts both physically and functionally with a Src family member, p56lck, and that p56lck activation leads to induction of the c-fos gene. However, the mechanism linking p56lck activation with c-fos induction remains unelucidated. In the present study, we systematically examined the extent of c-fos promoter activation by expression of a series of p56lck mutants, using a transient cotransfection assay. The results define a set of the essential amino acid residues that regulate p56lck induction of the c-fos promoter. We also provide evidence that the serum-responsive element and sis-inducible element are both targets through which p56lck controls c-fos gene activation.

scholarly journals c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses

2005 ◽  
Vol 391 (2) ◽  
pp. 153-166 ◽  
Author(s):  
Christine B. F. Thien ◽  
Wallace Y. Langdon
Keyword(s):  
Tyrosine Kinases ◽  
Ubiquitin Ligases ◽  
Adaptor Proteins ◽  
Kinase Domain ◽  
Protein Tyrosine Kinases ◽  
Tyrosine Kinase Domain ◽  
Transmembrane Receptors ◽  
Surface Receptors ◽  
Cbl Proteins ◽  
Initial Line

The activation of signalling pathways by ligand engagement with transmembrane receptors is responsible for determining many aspects of cellular function and fate. While these outcomes are initially determined by the nature of the ligand and its receptor, it is also essential that intracellular enzymes, adaptor proteins and transcription factors are correctly assembled to convey the intended response. In recent years, it has become evident that proteins that regulate the amplitude and duration of these signalling responses are also critical in determining the function and fate of cells. Of these, the Cbl family of E3 ubiquitin ligases and adaptor proteins has emerged as key negative regulators of signals from many types of cell-surface receptors. The array of receptors and downstream signalling proteins that are regulated by Cbl proteins is diverse; however, in most cases, the receptors have a common link in that they either possess a tyrosine kinase domain or they form associations with cytoplasmic PTKs (protein tyrosine kinases). Thus Cbl proteins become involved in signalling responses at a time when PTKs are first activated and therefore provide an initial line of defence to ensure that signalling responses proceed at the desired intensity and duration.

scholarly journals Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration

2015 ◽  
Vol 112 (43) ◽  
pp. 13225-13230 ◽  
Author(s):  
Sangwon Lee ◽  
Etienne B. Greenlee ◽  
Joseph R. Amick ◽  
Gwenda F. Ligon ◽  
Jay S. Lillquist ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tyrosine Kinases ◽  
Egf Receptor ◽  
Human Cancer ◽  
Extracellular Domain ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Fab Fragment ◽  
Allosteric Mechanism ◽  
Egfr Family

ErbB3 (HER3) is a member of the EGF receptor (EGFR) family of receptor tyrosine kinases, which, unlike the other three family members, contains a pseudo kinase in place of a tyrosine kinase domain. In cancer, ErbB3 activation is driven by a ligand-dependent mechanism through the formation of heterodimers with EGFR, ErbB2, or ErbB4 or via a ligand-independent process through heterodimerization with ErbB2 overexpressed in breast tumors or other cancers. Here we describe the crystal structure of the Fab fragment of an antagonistic monoclonal antibody KTN3379, currently in clinical development in human cancer patients, in complex with the ErbB3 extracellular domain. The structure reveals a unique allosteric mechanism for inhibition of ligand-dependent or ligand-independent ErbB3-driven cancers by binding to an epitope that locks ErbB3 in an inactive conformation. Given the similarities in the mechanism of ErbB receptor family activation, these findings could facilitate structure-based design of antibodies that inhibit EGFR and ErbB4 by an allosteric mechanism.

Sequencing the Multiple Myeloma Kinome: Absence of Mutation in Known Malignancy-Associated Kinases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 783-783
Author(s):  
Jaime O. Claudio ◽  
Razi Khaja ◽  
Lihua Zhuang ◽  
Meenakshi Bali ◽  
Kamalanayani Sivananthan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Amino Acid ◽  
Tyrosine Kinases ◽  
Genetic Disorder ◽  
Biological Significance ◽  
Kinase Domain ◽  
Genetic Alterations ◽  
Nucleotide Polymorphisms ◽  
Data Set ◽  
Recurrent Mutations

Abstract In approximately 50% of Multiple Myeloma (MM), translocation of non random genes into the IgH locus is believed to be the seminal event in the pathogenesis of the disease. Another 50% of cases are hyperdiploid and trisomic to certain autosomes, but do not harbor any translocation and thus are believed to have genetic alterations in unidentified loci. These observations, together with the finding of somatic mutations in FGFR3, N- and K-RAS, MYC, TP53 and CDKN2C/p18INK4C during the later stages of MM indicate that defective signaling pathways likely play a role in the progression of this malignancy. Of relevance then, in recent years recurrent mutations in kinases have frequently been implicated in malignancies including notably colon cancer and melanoma. We have therefore begun a comprehensive effort to sequence the tyrosine kinome for mutations and genetic polymorphisms in MM. Of particular interest are 90 receptor tyrosine kinases, 43 receptor tyrosine kinase-like, 5 receptor guanylate cyclase, and a lipid kinase. We report here results from our pilot high throughput exon scanning in 32 human MM cell lines which initially focused on 13 kinases known to be somatically mutated in human cancers. To date we have expanded this effort to assess 30 genes with sequence obtained which currently spans 80% coverage of the kinase domains of these genes. A total of 1.9 million bp have been sequenced across 235 exons. No recurrent mutations have been identified in the kinase domains of the cancer-associated genes: SRC, ILK1, KIT, GUCY2F, PDGFRA; in the genetic disorder-associated kinases: BTK, EPHA4, LAMA2, EPHB6, ACVR2; and in the mutation hot spots of frequently mutated cancer gene PIK3CA. A novel missense mutation is however identified upstream of the kinase domain of FGFR3 changing a Ser residue to Arg at codon 433. This residue, which is conserved across species and in FGFR1 and FGFR2, has not been reported in myeloma and in thanatophoric dysplasia, but the biological significance of this mutation is unknown. Several single nucleotide polymorphisms were identified in the coding regions of some of these kinases. Notably, synonymous polymorphisms in the kinase domains of EPHA4, PDGFRA3, KIT, MLK1, ILK1, NTRK3, FLT3, ABL1, FES, MLK4, and EGFR1 were identified that changed a codon but not the amino acid. More importantly, we identified non-synonymous amino acid variations in the kinase domains of EPHA4, GUCY2F, PTK2, and PIK3CA genes that are more likely to effect variability in the activity of these kinases. In summary, no recurrent kinase mutations of significance in Myeloma development or progression have yet been identified. Sequencing of the known cancer associated kinases in MGUS and hyperdiploid MM patients is now underway and our data set is being expanded to include all 139 kinases.

Association of IGF1R Polymorphisms with Growth Traits and its Expression Profiles in Different Pig Breeds

2020 ◽  
Author(s):  
Ying Bai ◽  
Xin Zhang ◽  
Qingyang Zhang ◽  
Yufang Liu ◽  
Xinxing Dong
Keyword(s):  
Growth Factor ◽  
Growth Traits ◽  
Expression Profiles ◽  
Average Daily Gain ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Growth Stages ◽  
Insulin Like Growth Factor ◽  
Nucleotide Polymorphisms ◽  
Pig Breeds

Insulin-like growth factor 1 receptor (IGF1R) is one component of insulin-like growth factor system, which has biological functions of growth traits. The aim of this study is to investigate the entire exons of IGF1R in the three commercial pig breeds, Duroc, Yorkshire and Landrace, to identify novel single nucleotide polymorphisms and their correlation with growth traits. One novel SNP (c.3678C>T) in the exon 20 was detected. This SNP caused the change of amino acid (Ser1217Phe), a portion of cytoplasmic tyrosine kinase domain of IGF1R. At the c.3678C>T site, three genotypes were significantly associated with average daily gain at different growth stage in Yorkshire and Landrace breeds. Meanwhile, we identified the differently expressed pattern of IGF1R in muscle of Yorkshire and Jinhua pigs at different growth stages. Our results provide useful information on understanding the effect of porcine IGF1R gene on growth. The novel IGF1R polymorphism may be useful as molecular markers in pig selection but future studies are required.

Characteristics of EGFR uncommon mutations in Chinese cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13527-e13527
Author(s):  
Minghui Wang ◽  
Shuben Li ◽  
Hongbiao Wang ◽  
Jianjiang Xie ◽  
Junhang Zhang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Kinase Domain ◽  
Copy Number Variations ◽  
Chinese Patients ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Lung Cancers ◽  
Exon 19

e13527 Background: Exon 19 deletions and exon 21 L858R substitutions are the most common mutations of epidermal growth factor receptor (EGFR) in cancers, and the remaining other mutations are called uncommon mutations. Recent studies have shown the clinical relevance of EGFR uncommon mutations with tyrosine kinase inhibitors (TKI) therapies and immunotherapies. Therefore, understanding the distribution and characteristics of EGFR uncommon mutations in cancers would provide evidence for future design of trials and drug development. Methods: Next-generation sequencing data were obtained from 3,026 Chinese tumor samples which have been identified with EGFR mutations. Single nucleotide variations (SNV), short and long insertions/deletions (indel), copy number variations and gene rearrangements were assessed. All tests were carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory in Shanghai, China. Results: EGFR mutations including 32% L858R substitutions, 28% exon 19 deletions, and 40% uncommon mutations were detected in this cohort. EGFR uncommon mutations were most frequently detected in lung cancers, followed by esophageal and gastric cancers. The uncommon mutations of EGFR including 54% SNVs, 30% amplifications, and 9% rare types of mutations such as rearrangement, long indels and complex mutations were detected. The SNVs in exon 18 to 21 which encode the tyrosine kinase domain of EGFR consisted of 16% EGFR mutations. Among them, the mostly frequently SNV was G719X in exon 18 and had 3% EGFR mutations. Mutations in other function domain of EGFR, including extracellular EGF binding domain (0.8%), transmembrane domain (0.03%) and intracellular autophosphorylation domain (0.7%) were also detected. Conclusions: Our data indicated that EGFR uncommon mutations were widely distributed in a variety of cancer types in Chinese patients, mostly in lung cancers. SNVs in the tyrosine kinase domain were the most frequent uncommon mutations. These data will provide clues for future clinical studies.

scholarly journals Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB

2020 ◽  
Vol 477 (20) ◽  
pp. 4053-4070
Author(s):  
Stephen C. Artim ◽  
Anatoly Kiyatkin ◽  
Mark A. Lemmon
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Catalytic Efficiency ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Signaling Dynamics ◽  
Cellular Context ◽  
And Function ◽  
High Degree

The tropomyosin-related kinase (Trk) family consists of three receptor tyrosine kinases (RTKs) called TrkA, TrkB, and TrkC. These RTKs are regulated by the neurotrophins, a class of secreted growth factors responsible for the development and function of neurons. The Trks share a high degree of homology and utilize overlapping signaling pathways, yet their signaling is associated with starkly different outcomes in certain cancers. For example, in neuroblastoma, TrkA expression and signaling correlates with a favorable prognosis, whereas TrkB is associated with poor prognoses. To begin to understand how activation of the different Trks can lead to such distinct cellular outcomes, we investigated differences in kinase activity and duration of autophosphorylation for the TrkA and TrkB tyrosine kinase domains (TKDs). We find that the TrkA TKD has a catalytic efficiency that is ∼2-fold higher than that of TrkB, and becomes autophosphorylated in vitro more rapidly than the TrkB TKD. Studies with mutated TKD variants suggest that a crystallographic dimer seen in many TrkA (but not TrkB) TKD crystal structures, which involves the kinase-insert domain, may contribute to this enhanced TrkA autophosphorylation. Consistent with previous studies showing that cellular context determines whether TrkB signaling is sustained (promoting differentiation) or transient (promoting proliferation), we also find that TrkB signaling can be made more transient in PC12 cells by suppressing levels of p75NTR. Our findings shed new light on potential differences between TrkA and TrkB signaling, and suggest that subtle differences in signaling dynamics can lead to substantial shifts in the cellular outcome.

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