Abstract
Receptor tyrosine kinases (RTKs) typically contain multiple autophosphorylation sites in their cytoplasmic domains. Once activated, these autophosphorylation sites can recruit downstream signaling proteins containing Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine-containing short linear motifs (SLiMs). These domains and SLiMs have polyspecific or promiscuous binding activities. Thus, multiple signaling proteins may compete for binding to a common SLiM and vice versa. To investigate the effects of competition on RTK signaling, we used a rule-based modeling approach to develop and analyze models for ligand-induced recruitment of SH2/PTB domain-containing proteins to autophosphorylation sites in the insulin-like growth factor 1 (IGF1) receptor (IGF1R). Models were parameterized using published datasets reporting protein copy numbers and site-specific binding affinities. Simulations were facilitated by a novel application of model restructuration, to reduce redundancy in rule-derived equations. We compare predictions obtained via numerical simulation of the model to those obtained through simple prediction methods, such as through an analytical approximation, or ranking by copy number and/or KD value, and find that the simple methods are unable to recapitulate the predictions of numerical simulations. We created 45 cell line-specific models that demonstrate how early events in IGF1R signaling depend on the protein abundance profile of a cell. Simulations, facilitated by model restructuration, identified pairs of IGF1R binding partners that are recruited in anti-correlated and correlated fashions, despite no inclusion of cooperativity in our models. This work shows that the outcome of competition depends on the physicochemical parameters that characterize pairwise interactions, as well as network properties, including network connectivity and the relative abundances of competitors.
Highlights
Cellular regulatory networks encompass conserved patterns of protein-protein interactions, which have been called network motifs [1,2]
To investigate the downstream signaling of a well-studied receptor tyrosine kinase (RTK), the insulin-like growth factor 1 (IGF1) receptor (IGF1R), we formulated and analyzed 45 cell line-specific mathematical models, which account for recruitment of 18 different binding partners to six sites of receptor autophosphorylation in IGF1R
In a given cell line, we find that pairs of IGF1R binding partners may be recruited in a correlated or anti-correlated fashion
Summary
Cellular regulatory networks encompass conserved patterns of protein-protein interactions, which have been called network motifs [1,2]. The motif consists of 1) a tyrosine residue within a protein, 2) a kinase that phosphorylates the tyrosine (termed a writer), 3) a phosphatase that dephosphorylates the phosphotyrosine product of kinase activity (termed an eraser), and 4) a protein containing a Src homology 2 (SH2) and/or phosphotyrosine binding (PTB) domain (termed a reader). SH2 and PTB domains are conserved modular structural units consisting of approximately 100 amino acids that have the ability to recognize and bind phosphotyrosine-containing short linear motifs (SLiMs) [5,6]. SH2 and PTB domains have preferences for specific SLiMs, which confers a degree of specificity in phosphotyrosine signaling [7]. Instances of these domains and SLiMs each have the potential to interact with multiple binding partners, a property that is sometimes referred to as binding promiscuity [12,13,14]
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