Receptor tyrosine kinases with intracellular pseudokinase domains

Mendrola, Jeannine M.; Shi, Feng; Park, Jin H.; Lemmon, Mark A.

doi:10.1042/bst20130104

Cited by 70 publications

(75 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A subgroup of receptor protein tyrosine kinases (RPTKs) is defective in tyrosine kinase activity because of alterations in motifs important for catalytic activity [1]. Such defective RPTKs include protein tyrosine kinase 7 (PTK7), HER3 (ErbB3), EphA10, EphB6, and Ryk.…”

Section: Introductionmentioning

confidence: 99%

Biphasic effect of PTK7 on KDR activity in endothelial cells and angiogenesis

Shin

Lee

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

Protein tyrosine kinase 7 (PTK7) is a member of the defective receptor protein tyrosine kinase family which lacks catalytic activity. Expression of PTK7 is increased in various cancers but its role in carcinogenesis is not well understood. We previously showed that disruption of PTK7 function suppresses VEGF-induced angiogenic phenotypes in HUVECs and mice. Here, we investigated molecular mechanisms for modulating VEGF-induced physiological effects by PTK7. Treatment with a high concentration of extracellular domain of PTK7 (soluble PTK7; sPTK7) or knockdown of PTK7 inhibited VEGF-induced phosphorylation of kinase insert domain receptor (KDR) but did not inhibit phosphorylation of fms-related tyrosine kinase 1 (FLT-1) in HUVECs. PTK7, more specifically sPTK7, interacted with KDR but not with FLT-1 in HUVECs and HEK293 cells. In vitro binding assay showed that sPTK7 formed oligomers with the extracellular domain of KDR (sKDR) up to an approximately 1:3 molar ratio, and vice versa. sPTK7 at lower molar ratios than sKDR enhanced the binding of VEGF to sKDR. At the same or higher molar ratios, it reduced the binding of VEGF to sKDR. Increasing concentrations of sPTK7 or increasing levels of PTK7 expression first increased and then decreased VEGF-induced KDR phosphorylation, migration, and capillary-like tube formation of HUVECs, as well as in vivo angiogenesis. Taken together, our data demonstrates that PTK7 regulates the activity of KDR biphasically by inducing oligomerization of KDR molecules at lower concentrations and by surrounding KDR molecules at higher concentrations.

show abstract

Section: Introductionmentioning

confidence: 99%

Biphasic effect of PTK7 on KDR activity in endothelial cells and angiogenesis

Shin

Lee

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

show abstract

“…For example, the ErbB2/ EGFR dimer (39,40,61), the JAK kinases where the pseudokinase domain of JAK interacts with and regulates the bona fide kinase domain of JAK (62), or the STRAD/Mo25 binding to AMPKK (32,33) could potentially induce cis autophosphorylation, helping to stabilize the active conformation.…”

Section: Figmentioning

confidence: 99%

Kinases and Pseudokinases: Lessons from RAF

Shaw

Kornev

et al. 2014

Molecular and Cellular Biology

135

113

View full text Add to dashboard Cite

Protein kinases are thought to mediate their biological effects through their catalytic activity. The large number of pseudokinases in the kinome and an increasing appreciation that they have critical roles in signaling pathways, however, suggest that catalyzing protein phosphorylation may not be the only function of protein kinases. Using the principle of hydrophobic spine assembly, we interpret how kinases are capable of performing a dual function in signaling. Its first role is that of a signaling enzyme (classical kinases; canonical), while its second role is that of an allosteric activator of other kinases or as a scaffold protein for signaling in a manner that is independent of phosphoryl transfer (classical pseudokinases; noncanonical). As the hydrophobic spines are a conserved feature of the kinase domain itself, all kinases carry an inherent potential to play both roles in signaling. This review focuses on the recent lessons from the RAF kinases that effectively toggle between these roles and can be "frozen" by introducing mutations at their hydrophobic spines.

show abstract

“…10,11 RORs are type I transmembrane receptors considered as pseudokinases due to alterations in their canonical tyrosine kinase motifs. 12,13 Apart from their critical roles in brain, heart, lung, and skeletal organogenesis as demonstrated by gene knockout studies in mice, 14 RORs have emerged as important players in cancer. ROR1 was shown to be expressed at high levels in several hematological malignancies such as chronic lymphocytic leukemia (CLL), MCL, chronic myelogenous leukemia, t(1;19) B-acute lymphoblastic leukemia (B-ALL), as well as many other solid tumors.…”

Section: Introductionmentioning

confidence: 99%