Multisite Phosphorylation Ubiquitination and Switch Like Responses

An important issue in the design of cell signaling networks is how protein-protein interactions can be used to integrate signals and create all-or-none responses. A typical

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Figure 2 (A) The Grb2 SH3-SH2-SH3 adaptor couples a pTyr-X-Asn docking site to multiple downstream targets through a series of protein-pro tein and protein-phospholipid interactions. One core pathway to cell growth is assembled through the N-terminal SH3 domain of Grb2 interacting with Pro-X-X-Pro motifs on the Ras-GTPase-activating protein Sos leading to MAP kinase activation. A second core pathway to cell survival is linked through the C-terminal SH3 domain of Grb2 binding to an Arg-X-X-Lys motif within the scaffolding protein Gabl. Ancillary control over this pathway is generated by the ShcA docking protein. ShcA acts, in part, to extend or amplify the functional potential of a receptor to recruit binding partners that convey signals. (B) The Shc docking protein serves as a prototypic example of evolved complexity in signal transduction within a conserved modular architecture. Shc evolution extends the binding capacity of the protein from a primordial form containing an SH2 and PTB domain flanking a central region containing an adaptin-binding and proline-rich section. Shc has gained in complexity, concomitantly with evolution from simple to complex multicellular organisms, by gaining increasing numbers of tyrosine residues that act as binding sites for SH2 domains of other proteins such as Grb2. In mammals, Shc has expanded to a three-gene family with additional forms created by alternate splicing of the ShcA mRNA. ShcB and ShcC are predominantly localized in the brain of mammals, perhaps reflecting the requirement for additional complexity in the signal transduction cascades in this tissue.

Figure 2 (A) The Grb2 SH3-SH2-SH3 adaptor couples a pTyr-X-Asn docking site to multiple downstream targets through a series of protein-pro tein and protein-phospholipid interactions. One core pathway to cell growth is assembled through the N-terminal SH3 domain of Grb2 interacting with Pro-X-X-Pro motifs on the Ras-GTPase-activating protein Sos leading to MAP kinase activation. A second core pathway to cell survival is linked through the C-terminal SH3 domain of Grb2 binding to an Arg-X-X-Lys motif within the scaffolding protein Gabl. Ancillary control over this pathway is generated by the ShcA docking protein. ShcA acts, in part, to extend or amplify the functional potential of a receptor to recruit binding partners that convey signals. (B) The Shc docking protein serves as a prototypic example of evolved complexity in signal transduction within a conserved modular architecture. Shc evolution extends the binding capacity of the protein from a primordial form containing an SH2 and PTB domain flanking a central region containing an adaptin-binding and proline-rich section. Shc has gained in complexity, concomitantly with evolution from simple to complex multicellular organisms, by gaining increasing numbers of tyrosine residues that act as binding sites for SH2 domains of other proteins such as Grb2. In mammals, Shc has expanded to a three-gene family with additional forms created by alternate splicing of the ShcA mRNA. ShcB and ShcC are predominantly localized in the brain of mammals, perhaps reflecting the requirement for additional complexity in the signal transduction cascades in this tissue.

enzymatic event, such as a kinase phosphorylating its substrate, or a simple binding event, such as an SH2 domain binding to a phosphorylated tyrosine site, conforms to Michaelis-Menton kinetics and therefore produces graded responses. In other words, the response to a given stimuls is initially linear and then tapers off in a hyperbolic manner (see Box l). This contrasts with digital switches in which a certain amount of stimulus converts the system from zero to a complete response. Some signaling pathways have steps at which noise is filtered out, signals are integrated, and all-or none decisions are made [53]. This is particularly important in key decisions such as progression through the cell cycle, when the cell must exercise precise control to avoid catastrophic events such as initiating DNA replication prematurely. One mechanism by which a signaling cascade can create a switch-like response (referred to as an ultrasensitive biological switch), is through the requirement for multiple, independent phospho-rylation events in order to sanction a requisite protein-protein interaction. Under these conditions, the response varies as a higher order of the kinase concentration, such that three independent phosphorylation events create a stimulus-response that responds to the third order of kinase concentration (modeled with a Hill coefficientof three). This has been observed biologically in a number of situations. In the maturation response of Xenopus oocytes, two independent phosphoryla-tion events within the MAP kinase pathway set up conditions for an all-or-none activation of the ERK MAP kinase [54]. In a related example, degradation of the yeast cyclin-dependent kinase (CDK) inhibitor Sicl, a key event required for the Gl to S transition (or START in the cell cycle), requires six of nine serine/threonine phosphorylation sites on Sicl to be phosphorylated by the CDK activity present in the Gl phase of the cell cycle in order for Sicl to be targeted for ubiquiti-nation and degradation. Phosphorylated Sicl is bound by the WD40 repeat domain of an F-box protein, Cdc4, that serves as the substrate binding subunit of an E3 protein-ubiquitin ligase complex. Thus, Sicl acts to monitor G1 CDK activity, setting a threshold for kinase activity that must be met in order for START to occur [55]. In this case, multisite phosphoryla-tion, coupled with a simple binary interaction, creates an ultrasensitive response that ensures the orderly and timely transition into the S phase of the cell cycle [56,57]. In both Xenopus maturation factor response and yeast cell-cycle progression, additional factors may conspire to create extremely sharp switch-like responses.

A corollary to these observations is that phosphorylation of proteins on serine/threonine residues induces protein ubiquitination and destruction. The phosphorylated target is

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