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.

Regulation of class IA PI3Ks

2007 ◽  
Vol 35 (2) ◽  
pp. 242-244 ◽  
Author(s):  
H. Wu ◽  
Y. Yan ◽  
J.M. Backer
Keyword(s):  
Tyrosine Kinases ◽  
Regulatory Subunit ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Pi3k Activity ◽  
Wide Range ◽  
Rho Family Gtpases ◽  
Src Homology ◽  
Rho Family

Class IA PI3Ks (phosphoinositide 3-kinases) regulate a wide range of cellular responses through the production of PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate) in cellular membranes. They are activated by receptor tyrosine kinases, by Ras and Rho family GTPases, and in some cases by Gβγ subunits from trimeric G-proteins. Crystallographic studies on the related class IB PI3Kγ, and biochemical and structural studies on the class IA PI3Ks, have led to new insights into how these critical enzymes are regulated in normal cells and how mutations can lead to their constitutive activation in transformed cells. The present paper will discuss recent studies on the regulation of class I (p85/p110) PI3Ks, with a focus on the role of SH2 domains (Src homology 2 domains) in the p85 regulatory subunit in modulating PI3K activity.

scholarly journals The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain

2019 ◽  
Vol 116 (30) ◽  
pp. 14979-14988 ◽  
Author(s):  
Sven H. Schmidt ◽  
Matthias J. Knape ◽  
Daniela Boassa ◽  
Natascha Mumdey ◽  
Alexandr P. Kornev ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Regulatory Mechanism ◽  
Kinase Domain ◽  
Leucine Rich Repeat ◽  
Wild Type ◽  
Conformational Switch ◽  
Multidomain Protein ◽  
Switch Mechanism ◽  
And Function

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein, and LRRK2 mutants are recognized risk factors for Parkinson’s disease (PD). Although the precise mechanisms that control LRRK2 regulation and function are unclear, the importance of the kinase domain is strongly implicated, since 2 of the 5 most common familial LRRK2 mutations (G2019S and I2020T) are localized to the conserved DFGψ motif in the kinase core, and kinase inhibitors are under development. Combining the concept of regulatory (R) and catalytic (C) spines with kinetic and cell-based assays, we discovered a major regulatory mechanism embedded within the kinase domain and show that the DFG motif serves as a conformational switch that drives LRRK2 activation. LRRK2 is quite unusual in that the highly conserved Phe in the DFGψ motif, which is 1 of the 4 R-spine residues, is replaced with tyrosine (DY2018GI). A Y2018F mutation creates a hyperactive phenotype similar to the familial mutation G2019S. The hydroxyl moiety of Y2018 thus serves as a “brake” that stabilizes an inactive conformation; simply removing it destroys a key hydrogen-bonding node. Y2018F, like the pathogenic mutant I2020T, spontaneously forms LRRK2-decorated microtubules in cells, while the wild type and G2019S require kinase inhibitors to form filaments. We also explored 3 different mechanisms that create kinase-dead pseudokinases, including D2017A, which further emphasizes the highly synergistic role of key hydrophobic and hydrophilic/charged residues in the assembly of active LRRK2. We thus hypothesize that LRRK2 harbors a classical protein kinase switch mechanism that drives the dynamic activation of full-length LRRK2.

Proteins with SH2 and SH3 domains couple receptor tyrosine kinases to intracellular signalling pathways

1993 ◽  
Vol 340 (1293) ◽  
pp. 279-285 ◽  
Keyword(s):  
Protein Interactions ◽  
Tyrosine Kinases ◽  
Receptor Protein ◽  
Signalling Pathways ◽  
Protein Protein Interactions ◽  
Sh3 Domains ◽  
Ras Pathway ◽  
Sh2 Domains ◽  
Intracellular Signalling Pathways ◽  
Src Homology

The targets of receptor protein-tyrosine kinases are characterized by Src homology 2 (SH2) domains, that mediate specific interactions with receptor autophosphorylation sites. SH 2-mediated interactions are important for the activation of biochemical signalling pathways in cells stimulated with growth factors. A distinct protein module, the SH3 domain, is frequently found in polypeptides that contain SH2 domains, and is also implicated in controlling protein-protein interactions in signal transduction. Evidence suggesting that SH2 and SH3 domains act synergistically in stimulation of the Ras pathway is discussed.

scholarly journals The common src homology region 2 domain of cytoplasmic signaling proteins is a positive effector of v-fps tyrosine kinase function.

1989 ◽  
Vol 9 (10) ◽  
pp. 4131-4140 ◽  
Author(s):  
C A Koch ◽  
M Moran ◽  
I Sadowski ◽  
T Pawson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Specific Activity ◽  
Intramolecular Interaction ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Homology Region ◽  
Src Homology ◽  
Type V

A conserved noncatalytic domain SH2 (for src homology region 2) is located immediately N terminal to the kinase domains of all cytoplasmic protein-tyrosine kinases. We found that the wild-type v-fps SH2 domain stimulated the enzymatic activity of the adjacent kinase domain 10-fold and functioned as a powerful positive effector of catalytic and transforming activities within the v-fps oncoprotein (P130gag-fps). Partial proteolysis of P130gag-fps and supporting genetic data indicated that the v-fps SH2 domain exerts its effect on catalytic activity through an intramolecular interaction with the kinase domain. Amino acid alterations in the SH2 domain that impaired kinase function interfered with association of the SH2 domain with the kinase domain. Deletion of a conserved octapeptide motif converted the v-fps SH2 domain from an activator to an inhibitor of tyrosine kinase activity. This latent inhibitory activity of v-fps SH2 has functional implications for phospholipase C-gamma and p21ras GTPase-activating protein, both of which have two distinct SH2 domains suggestive of complex regulation. In addition to regulating the specific activity of the kinase domain, the SH2 domain of P130gag-fps was also found to be required for the tyrosine phosphorylation of specific cellular proteins, notably polypeptides of 124 and 62 kilodaltons. The SH2 domain therefore appears to play a dual role in regulation of kinase activity and recognition of cellular substrates.

scholarly journals The Role of Phosphotyrosine Signaling Pathway in Parotid Gland Proliferation and Function

1995 ◽  
Vol 6 (2) ◽  
pp. 119-131 ◽  
Author(s):  
K.R. Purushotham ◽  
M.G. Humphreys-Beher
Keyword(s):  
Salivary Glands ◽  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Potential Role ◽  
Biological Processes ◽  
Secretory Function ◽  
Phosphotyrosine Signaling ◽  
And Function ◽  
Active Proliferation

Tyrosine phosphorylation and the intracellular signaling processes associated with it have been the focus of intense study due to its importance in the regulation of biological processes as diverse as cell proliferation and cell differentiation. While much of what we now understand has been derived from the study of cell lines and tumor cells, the salivary glands provide a model to examine the effects of tyrosine kinases and tyrosine phosphatases in a normal differentiated tissue. This review will focus, therefore, on the role tyrosine kinases and phosphatases play in inducing the transition from stasis to active proliferation and their potential role in mediating secretory function of the salivary glands.

scholarly journals Nbr1 Is a Novel Inhibitor of Ligand-Mediated Receptor Tyrosine Kinase Degradation

2010 ◽  
Vol 30 (24) ◽  
pp. 5672-5685 ◽  
Author(s):  
Faraz K. Mardakheh ◽  
Giulio Auciello ◽  
Tim R. Dafforn ◽  
Joshua Z. Rappoport ◽  
John K. Heath
Keyword(s):  
Tyrosine Kinases ◽  
Protein Localization ◽  
Negative Regulator ◽  
Receptor Internalization ◽  
C Terminus ◽  
Late Endosomes ◽  
Exact Function ◽  
Α Helix ◽  
And Function

ABSTRACT Neighbor of BRCA1 (Nbr1) is a highly conserved multidomain scaffold protein with proposed roles in endocytic trafficking and selective autophagy. However, the exact function of Nbr1 in these contexts has not been studied in detail. Here we investigated the role of Nbr1 in the trafficking of receptor tyrosine kinases (RTKs). We report that ectopic Nbr1 expression inhibits the ligand-mediated lysosomal degradation of RTKs, and this is probably done via the inhibition of receptor internalization. Conversely, the depletion of endogenous NBR1 enhances RTK degradation. Analyses of truncation mutations demonstrated that the C terminus of Nbr1 is essential but not sufficient for this activity. Moreover, the C terminus of Nbr1 is essential but not sufficient for the localization of the protein to late endosomes. We demonstrate that the C terminus of Nbr1 contains a novel membrane-interacting amphipathic α-helix, which is essential for the late endocytic localization of the protein but not for its effect on RTK degradation. Finally, autophagic and late endocytic localizations of Nbr1 are independent of one another, suggesting that the roles of Nbr1 in each context might be distinct. Our results define Nbr1 as a negative regulator of ligand-mediated RTK degradation and reveal the interplay between its various regions for protein localization and function.

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.

The common src homology region 2 domain of cytoplasmic signaling proteins is a positive effector of v-fps tyrosine kinase function

1989 ◽  
Vol 9 (10) ◽  
pp. 4131-4140
Author(s):  
C A Koch ◽  
M Moran ◽  
I Sadowski ◽  
T Pawson
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Specific Activity ◽  
Intramolecular Interaction ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Homology Region ◽  
Src Homology ◽  
Type V

A conserved noncatalytic domain SH2 (for src homology region 2) is located immediately N terminal to the kinase domains of all cytoplasmic protein-tyrosine kinases. We found that the wild-type v-fps SH2 domain stimulated the enzymatic activity of the adjacent kinase domain 10-fold and functioned as a powerful positive effector of catalytic and transforming activities within the v-fps oncoprotein (P130gag-fps). Partial proteolysis of P130gag-fps and supporting genetic data indicated that the v-fps SH2 domain exerts its effect on catalytic activity through an intramolecular interaction with the kinase domain. Amino acid alterations in the SH2 domain that impaired kinase function interfered with association of the SH2 domain with the kinase domain. Deletion of a conserved octapeptide motif converted the v-fps SH2 domain from an activator to an inhibitor of tyrosine kinase activity. This latent inhibitory activity of v-fps SH2 has functional implications for phospholipase C-gamma and p21ras GTPase-activating protein, both of which have two distinct SH2 domains suggestive of complex regulation. In addition to regulating the specific activity of the kinase domain, the SH2 domain of P130gag-fps was also found to be required for the tyrosine phosphorylation of specific cellular proteins, notably polypeptides of 124 and 62 kilodaltons. The SH2 domain therefore appears to play a dual role in regulation of kinase activity and recognition of cellular substrates.

scholarly journals The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase.

1995 ◽  
Vol 15 (8) ◽  
pp. 4453-4465 ◽  
Author(s):  
S Pons ◽  
T Asano ◽  
E Glasheen ◽  
M Miralpeix ◽  
Y Zhang ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Regulatory Subunit ◽  
Stable Complex ◽  
Phosphatidylinositol 3 Kinase ◽  
Sh2 Domains ◽  
Cellular Processes ◽  
Src Homology 2 ◽  
Src Homology ◽  
And Function ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-kinase (PI-3 kinase) is implicated in the regulation of diverse cellular processes, including insulin-stimulated glucose transport. PI-3 kinase is composed of a 110-kDa catalytic subunit and an 85-kDa regulatory subunit. Here, we describe p55PIK, a new regulatory subunit that was isolated by screening expression libraries with tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1). p55PIK is composed of a unique 30-residue NH2 terminus followed by a proline-rich motif and two Src homology 2 (SH2) domains with significant sequence identify to those in p85. p55PIK mRNA is expressed early during development, remains abundant in adult mouse brain and testis tissue, and is detectable in adult adipocytes and heart and kidney tissues. p55PIK forms a stable complex with p110, and it associates with IRS-1 during insulin stimulation. Moreover, the activated insulin receptor phosphorylates p55PIK in Sf9 cells, and insulin stimulates p55PIK phosphorylation in CHOIR/p55PIK cells. The unique features of p55PIK suggest that it is important in receptor signaling.

scholarly journals The kinase, SH3, and SH2 domains of Lck play critical roles in T-cell activation after ZAP-70 membrane localization.

1996 ◽  
Vol 16 (12) ◽  
pp. 7151-7160 ◽  
Author(s):  
S Yamasaki ◽  
M Takamatsu ◽  
M Iwashima
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Chimeric Protein ◽  
Activated T Cells ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Signaling Process

Antigenic stimulation of the T-cell antigen receptor initiates signal transduction through the immunoreceptor tyrosine-based activation motifs (ITAMs). When its two tyrosines are phosphorylated, ITAM forms a binding site for ZAP-70, one of the cytoplasmic protein tyrosine kinases essential for T-cell activation. The signaling process that follows ZAP-70 binding to ITAM has been analyzed by the construction of fusion proteins that localize ZAP-70 to the plasma membrane. We found that membrane-localized forms of ZAP-70 induce late signaling events such as activation of nuclear factor of activated T cells without any stimulation. This activity was observed only when Lck was expressed and functional. In addition, each mutation that affects the function of Lck in the kinase, Src homology 2 (SH2), and SH3 domains greatly impaired the signaling ability of the chimeric protein. Therefore, Lck functions in multiple manners in T-cell activation for the steps following ZAP-70 binding to ITAM.

Sign in / Sign up

Export Citation Format

Share Document