SIG Projects Suggested Project Idea: Model recruitment of signaling proteins (with SH2 domains) to a receptor tyrosine kinase (RTK) in different cell.

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Presentation transcript:

SIG Projects Suggested Project Idea: Model recruitment of signaling proteins (with SH2 domains) to a receptor tyrosine kinase (RTK) in different cell lines Mentor: Bill Hlavacek

RTKs (2 out of 3 tyrosine kinases in human genome) https://www.ncbi.nlm.nih.gov/pubmed/20602996

Mechanisms of activation https://www.ncbi.nlm.nih.gov/pubmed/20602996

GRB2 2885 P62993 FGFR3 Y724 2261 P22607 KPANCTHDLyMIMRECW 0.76250561 FLT1 Y1213 2321 P17948 NSGSSDDVRyVNAFKFM 0.366702476 INSR Y1011 3643 P06213 ASDVFPCSVyVPDEWEV 0.807896663 KIT Y936 3815 P10721 QISESTNHIySNLANCS 0.406433417 MET Y1313 4233 P08581 QPEYCPDPLyEVMLKCW 0.907739649 Y1356 EHYVHVNATyVNVKCVA 0.262135773 MST1R Y1317 4486 Q04912 QPEYCPDSLyQVMQQCW 0.970287321 RET Y1096 5979 P07949 FPRYPNDSVyANWMLSP 0.158620832 TEK Y1113 7010 Q02763 NTTLYEKFTyAGIDCSA 0.954262799 FRS2 Y196 10818 Q8WU20 LVAEEQVHTyVNTTGVQ 0.761345709 EGFR Y1092 1956 P00533 DDTFLPVPEyINQSVPK 0.312084656 Y1138 HSTAVGNPEyLNTVQPT 0.382719924 https://www.ncbi.nlm.nih.gov/pubmed/23358503 https://www.ncbi.nlm.nih.gov/pubmed/25863072

Protein copy numbers vary from cell type to cell type https://www.ncbi.nlm.nih.gov/pubmed/22278370

Absolute quantification of protein abundances in HeLa Kyoto cells https://www.ncbi.nlm.nih.gov/pubmed/26496610

Predicted levels of recruitment to EGFR based on measured KD’s and protein copy numbers for HeLa S3 cells https://www.ncbi.nlm.nih.gov/pubmed/25863072

Variability in (predicted) recruitment across cell lines Kulak et al Geiger et al HeLa A549 GAMG HEK293 HepG2 Jurkat K562 LnCap MCF7 RKO U2OS SHC1 SRC GRB2 LCK PLCG1 RASA1 YES1 GRAP2 SH2B3 PTPN11* PTPN11 VAV2 SOCS6 SH2D2A* SRC* SLA2 VAV2** PIK3R2 PIK3R1 YES1** VAV3 PIK3R3 SH2D2A VAV1* PIK3R1** PIK3R2* SH2B2 GRB7 PIK3R1*** VAV2* PTK6 PIK3R2*** SH2B3*** SHB PIK3R2** VAV3*** VAV3* VAV1*** PIK3R3** VAV1 BLK SHB* PLCG1** TEC SLA2*** VAV2*** HSH2D https://www.ncbi.nlm.nih.gov/pubmed/25863072

Suggested steps Pick an RTK (don’t pick EGFR, IGF1R, or TrkA) Develop a simple model for RTK dimerization by ligand ID sites of autophosphorylation in RTK Find KD’s for these sites and SH2/PTB domains Find protein copy number measurements for RTK binding partners for multiple cell lines Add autophosphorylation to model Add recruitment of SH2/PTB domain-containing proteins to pY’s Predict relative levels of recruitment for different cell lines

Questions? E-mail: wshlavacek@gmail.com or wish@lanl.gov iPhone: 505-500-7327