Mitchell J. Geer
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View article: T lymphocyte–specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4 <sup>+</sup> T cells and impairs antitumor response
T lymphocyte–specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4 <sup>+</sup> T cells and impairs antitumor response Open
SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSM…
View article: T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response
T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response Open
SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSM…
LAIR-1 and PECAM-1 function via the same signaling pathway to inhibit GPVI-mediated platelet activation Open
Findings from this study reveal that LAIR-1 and PECAM-1 act to inhibit GPVI-mediated platelet activation via the same signaling pathway. Mice lacking LAIR-1 and PECAM-1 do not however exhibit an increase in thrombus formation despite minor…
Supplementary Method from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Detailed Supplementary Method
Supplementary table and figure legends from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Supplementary table and figure legends
Data from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 …
Figure S1-S7 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Supplementary Figure S1: Combined SHP2/MEK inhibition prevents adaptive resistance in PDAC and NSCLC lines Supplementary Figure S2: SHP2 inhibition abrogates MEK-I-evoked reactivation of the ERK MAPK pathway Supplementary Figure S3: Distin…
Supplementary Method from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Detailed Supplementary Method
Data from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 …
Supplementary table and figure legends from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Supplementary table and figure legends
Table S1 and S2 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Table S1: Bliss Index for Effect of MEK-I/SHP099 Combination on Cancer Cell Proliferation Table S2: Primer Sequences for qRT-PCR
Figure S1-S7 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Supplementary Figure S1: Combined SHP2/MEK inhibition prevents adaptive resistance in PDAC and NSCLC lines Supplementary Figure S2: SHP2 inhibition abrogates MEK-I-evoked reactivation of the ERK MAPK pathway Supplementary Figure S3: Distin…
Table S1 and S2 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Table S1: Bliss Index for Effect of MEK-I/SHP099 Combination on Cancer Cell Proliferation Table S2: Primer Sequences for qRT-PCR
Genome-wide CRISPR/Cas9 screens reveal shared and cell-specific mechanisms of resistance to SHP2 inhibition Open
SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric SHP2 inhibitors (SHP2i) in the clinic prevent SHP2 activation, block proliferation of RTK- or cycling RAS mutant-driven cancers, and overcome “adaptive resistance.”…
View article: Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B–deficient mice
Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B–deficient mice Open
Mice lacking the immunoreceptor tyrosine-based inhibition motif-containing co-inhibitory receptor G6b-B (Mpig6b, G6b knockout, KO) are born with a complex megakaryocyte (MK) per platelet phenotype, characterized by severe macrothrombocytop…
Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition Open
SHP2 ( PTPN11 ) acts upstream of SOS1/2 to enable RAS activation. Allosteric inhibitors (SHP2is) stabilize SHP2 auto-inhibition, preventing activation by upstream stimuli. SHP2is block proliferation of RTK- or cycling RAS mutant-driven can…
View article: SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling Open
KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C a…
View article: SHP2 Inhibition Abrogates Adaptive Resistance to KRAS<sup>G12C</sup>-Inhibition and Remodels the Tumor Microenvironment of<i>KRAS</i>-Mutant Tumors
SHP2 Inhibition Abrogates Adaptive Resistance to KRAS<sup>G12C</sup>-Inhibition and Remodels the Tumor Microenvironment of<i>KRAS</i>-Mutant Tumors Open
KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime therapeutic goal. Recently, inhibitors (G12C-Is) that bind KRAS G12C -GDP and react with Cys-12 were developed. Using new affinity reagen…
View article: Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B
Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B Open
The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in …
View article: Comparative Analysis of Microfluidics Thrombus Formation in Multiple Genetically Modified Mice: Link to Thrombosis and Hemostasis
Comparative Analysis of Microfluidics Thrombus Formation in Multiple Genetically Modified Mice: Link to Thrombosis and Hemostasis Open
Genetically modified mice are indispensable for establishing the roles of platelets in arterial thrombosis and hemostasis. Microfluidics assays using anticoagulated whole blood are commonly used as integrative proxy tests for platelet func…
Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B Open
The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation, loss of which results in severe macrothrombocytopenia and aberrant platelet function in mice and humans…
The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions Open
Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Platelet factor 4-Cre recombinase (Pf4-Cre) transgenic mouse is the current model of choice for generating megakaryocyte/platel…
SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models Open
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 …
Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice Open
Key Points Autosomal recessive loss-of-function mutations in G6b-B (MPIG6B) cause congenital macrothrombocytopenia with focal myelofibrosis. G6b-B has orthologous physiological functions in human and mice regulating megakaryocyte and plate…
Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis Open
Publisher's Note: There is a Blood Commentary on this article in this issue.
Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148 Open
Key Points Csk and CD148 are nonredundant regulators of SFKs in platelets, and deletion of either induces cell-intrinsic negative feedback mechanisms. Csk is a negative regulator of SFK activity, whereas CD148 is a dual positive and negati…
ITIM receptors: more than just inhibitors of platelet activation Open
Since their discovery, immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptors have been shown to inhibit signaling from immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors in almost all hematopoie…