Corrigendum to: "Task syndromes: linking personality and task allocation in social animal groups" by J. C. Loftus, A. Perez, and A. Sih. 32:1-17.

[This corrects the article DOI: 10.1093/beheco/araa083.].

Task syndromes: linking personality and task allocation in social animal groups.

Studies of eusocial insects have extensively investigated two components of task allocation: how individuals distribute themselves among different tasks in a colony and how the distribution of labor changes to meet fluctuating task demand. While discrete age- and morphologically-based task allocation systems explain much of the social order in these colonies, the basis for task allocation in non-eusocial organisms and within eusocial castes remains unknown. Building from recent advances in the study of among-individual variation in behavior (i.e., animal personalities), we explore a potential mechanism by which individuality in behaviors unrelated to tasks can guide the developmental trajectories that lead to task specialization. We refer to the task-based behavioral syndrome that results from the correlation between the antecedent behavioral tendencies and task participation as a task syndrome. In this review, we present a framework that integrates concepts from a long history of task allocation research in eusocial organisms with recent findings from animal personality research to elucidate how task syndromes and resulting task allocation might manifest in animal groups. By drawing upon an extensive and diverse literature to evaluate the hypothesized framework, this review identifies future areas for study at the intersection of social behavior and animal personality.

Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells.

Elevated focal adhesion kinase (FAK) expression in human tumor cells has been correlated with an increased cell invasion potential. In cell culture, studies with FAK-null fibroblasts have shown that FAK function is required for cell migration. To determine the role of elevated FAK expression in facilitating epidermal growth factor (EGF)-stimulated human adenocarcinoma (A549) cell motility, antisense oligonucleotides were used to reduce FAK protein expression >75%. Treatment of A549 cells with FAK antisense (ISIS 15421) but not a mismatched control (ISIS 17636) oligonucleotide resulted in reduced EGF-stimulated p130(Cas)-Src complex formation, c-Jun NH(2)-terminal kinase (JNK) activation, directed cell motility, and serum-stimulated cell invasion through Matrigel. Because residual FAK protein in ISIS 15421-treated A549 cells was highly phosphorylated at the Tyr-397/Src homology (SH)2 binding site, expression of the FAK COOH-terminal domain (FRNK) was also used as an inhibitor of FAK function. Adenoviral-mediated infection and expression of FRNK promoted FAK dephosphorylation at Tyr-397, resulted in reduced EGF-stimulated JNK as well as extracellular-regulated kinase 2 (ERK2) kinase activation, inhibited matrix metalloproteinase-9 (MMP-9) secretion, and potently blocked both random and EGF-stimulated A549 cell motility. Equivalent expression of a FRNK (S-1034) point-mutant that did not promote FAK dephosphorylation also did not affect EGF-stimulated signaling or cell motility. Dose-dependent reduction in EGF-stimulated A549 motility was observed with the PD98059 MEK1 inhibitor and the batimastat (BB-94) inhibitor of MMP activity, but not with the SB203580 inhibitor of p38 kinase. Finally, comparisons between normal, FAK-null, and FAK-reconstituted fibroblasts revealed that FAK enhanced EGF-stimulated JNK and ERK2 kinase activation that was required for cell motility. These data indicate that FAK functions as an important signaling platform to coordinate EGF-stimulated cell migration in human tumor cells and support a role for inhibitors of FAK expression or activity in the control of neoplastic cell invasion.

Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance.

The molecular mechanisms that regulate the cardiac hypertrophic response and the progression from compensated hypertrophy to decompensated heart failure have not been thoroughly defined. Alteration in cardiac extracellular matrix is a distinguishing characteristic of these pathological processes. Integrins, cell surface receptors that mediate cellular adhesion to the extracellular matrix, are signaling molecules that possess mechanotransduction properties. Therefore, we hypothesized that integrins are likely candidates to play an important role in cardiac function. To test this hypothesis, transgenic mice were constructed in which normal integrin function was disrupted by expression of a chimeric molecule encoding the transmembrane and extracellular domains of the Tac subunit of the IL-2 receptor, fused to the cytoplasmic domain of beta(1A) integrin (Tacbeta(1A)). Using the alpha myosin heavy chain promoter to target expression of this chimera to the cardiac myocyte, transgenic mice were generated that had varied levels of transgene expression. Multiple transgenic founders that expressed the transgene at high levels, died perinatally and exhibited replacement fibrosis. Lines that survived showed 1) hypertrophic changes concordant with reduction in endogenous beta(1) integrin levels, or 2) reduced basal contractility and relaxation as well as alterations in components of integrin signaling pathways. These data support an important role for beta(1) integrin in normal cardiac function.

Autoantibodies to alpha(IIb)beta(3) in patients with chronic immune thrombocytopenic purpura bind primarily to epitopes on alpha(IIb).

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease caused by platelet destruction resulting from autoantibodies against platelet surface proteins, particularly platelet glycoprotein IIb/IIIa (alpha(IIb)beta(3)). To localize the auto-epitopes on platelet alpha(IIb)beta(3), the binding of autoantibodies to Chinese hamster ovary (CHO) cells expressing either alpha(IIb)beta(3) or alpha(v)beta(3) was studied. Thirteen of 14 ITP autoantibodies bound only to CHO cells expressing alpha(IIb)beta(3). Because these 2 integrins have the same beta chain (beta(3)), these results show that most epitopes in chronic ITP are dependent on the presence of glycoprotein alpha(IIb.) (Blood. 2001;97:2171-2172)

Striated muscle-specific beta(1D)-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway.

Alterations in the extracellular matrix occur during the cardiac hypertrophic process. Because integrins mediate cell-matrix adhesion and beta(1D)-integrin (beta1D) is expressed exclusively in cardiac and skeletal muscle, we hypothesized that beta1D and focal adhesion kinase (FAK), a proximal integrin-signaling molecule, are involved in cardiac growth. With the use of cultured ventricular myocytes and myocardial tissue, we found the following: 1) beta1D protein expression was upregulated perinatally; 2) alpha(1)-adrenergic stimulation of cardiac myocytes increased beta1D protein levels 350% and altered its cellular distribution; 3) adenovirally mediated overexpression of beta1D stimulated cellular reorganization, increased cell size by 250%, and induced molecular markers of the hypertrophic response; and 4) overexpression of free beta1D cytoplasmic domains inhibited alpha(1)-adrenergic cellular organization and atrial natriuretic factor (ANF) expression. Additionally, FAK was linked to the hypertrophic response as follows: 1) coimmunoprecipitation of beta1D and FAK was detected; 2) FAK overexpression induced ANF-luciferase; 3) rapid and sustained phosphorylation of FAK was induced by alpha(1)-adrenergic stimulation; and 4) blunting of the alpha(1)-adrenergically modulated hypertrophic response was caused by FAK mutants, which alter Grb2 or Src binding, as well as by FAK-related nonkinase, a dominant interfering FAK mutant. We conclude that beta1D and FAK are both components of the hypertrophic response pathway of cardiac myocytes.

Differential recognition of snake venom proteins expressing specific Arg-Gly-Asp (RGD) sequence motifs by wild-type and variant integrin alphaIIbbeta3: further evidence for distinct sites of RGD ligand recognition exhibiting negative allostery.

Several studies have demonstrated that the amino acid residues flanking the Arg-Gly-Asp (RGD) sequence of high-affinity ligands modulate their specificity of interaction with integrin complexes. Because of the absence of structural data for integrin complexes with bound ligand, the molecular basis for this specificity modulation remains obscure. In a previous paper [Rahman, Lu, Kakkar and Authi (1995) Biochem. J. 312, 223-232] we demonstrated that two genetically distinct venom-derived RGD proteins, kistrin and dendroaspin (both containing the sequence PRGDMP), were simple competitors, indicating the recognition of an identical binding site on the alpha(IIb)beta(3) complex. Furthermore, both kistrin and dendroaspin inhibited the binding of the disintegrin elegantin (containing the sequence ARGDNP) via a non-competitive mechanism, suggesting that the binding of elegantin to the alpha(IIb)beta(3) complex was at a remote site and down-regulated via an allosteric mechanism. Here we present further evidence for distinct RGD ligand recognition sites on the alpha(IIb)beta(3) complex that exhibit a negative allosteric relationship. A panel of well-characterized recombinant dendroaspin and elegantin derivatives were employed for this study. These recombinant molecules were constructed as glutathione S-transferase fusion proteins with either an Ala or Pro residue N-terminal to the RGD sequence in combination with either a Met or an Asn residue immediately C-terminal. Equilibrium competition experiments showed that elegantin binding to ADP-treated platelets was inhibited by derivatives Eleg. AM (ARGDMP) and Eleg. PM (PRGDMP) via an allosteric competitive mechanism, providing direct evidence that modulation of the RGD motif can alter competitive behaviour. In addition, recombinant kistrin and dendroaspin both inhibited elegantin binding via a non-competitive mechanism, confirming our previous observations. Further evidence for distinct binding sites employing an independent approach was obtained by analysing the binding of the panel of venom proteins to the functionally defective heterodimer alpha(IIb)beta(3) Ser(123)-->Ala expressed on Chinese hamster ovary cells. These studies demonstrated that simple competitors kistrin and dendroaspin bound with high affinity to the variant integrin complex. In contrast, the binding of elegantin and most significantly, recombinant Dendro. PN (PRGDNP) and Dendro. AN (ARGDNP) were abolished. These observations, taken together, are consistent with a model depicting the presence of distinct sites of RGD ligand recognition on the alpha(IIb)beta(3) complex that show the preferential recognition of specific RGD motifs. Competition experiments demonstrate a negative allosteric relationship between these RGD recognition sites.

A mutation in the alpha subunit of the platelet integrin alphaIIbbeta3 identifies a novel region important for ligand binding.

An unbiased genetic approach was used to identify a specific amino acid residue in the alphaIIb subunit important for the ligand binding function of the integrin alphaIIbbeta. Chemically mutagenized cells were selected by flow cytometry based on their inability to bind the ligand mimetic antibody PAC1 and a cell line containing a single amino acid substitution in alphaIIb at position 224 (D-->V) was identified. Although well expressed on the surface of transfected cells, alphaIIbD224Vbeta3 as well as alphaIIbD224Abeta3 did not bind alphaIIbbeta3-specific ligands or a RGD peptide, a ligand shared in common with alphavbeta3. Insertion of exon 5 of alphaIIb, residues G193-W235, into the backbone of the alphav subunit did not enable the chimeric receptor to bind alphaIIbbeta3-specific ligands. However, the chimeric receptor was still capable of binding to a RGD affinity matrix. alphaIIbD224 is not well conserved among other integrin alpha subunits and is located in a region of significant variability. In addition, amino acid D224 lies within a predicted loop of the recently proposed beta-propeller model for integrin alpha subunits and is adjacent to a loop containing amino acid residues previously implicated in receptor function. These data support a role for this region in ligand binding function of the alphaIIbbeta3 receptor.

Beta1 integrins participate in the hypertrophic response of rat ventricular myocytes.

Multiple signaling pathways have been implicated in the hypertrophic response of ventricular myocytes, yet the importance of cell-matrix interactions has not been extensively examined. Integrins are cell-surface molecules that link the extracellular matrix to the cellular cytoskeleton. They can function as cell signaling molecules and transducers of mechanical information in noncardiac cells. Given these properties and their abundance in cardiac cells, we evaluated the hypothesis that beta1 integrin function is involved in the alpha1-adrenergic mediated hypertrophic response of neonatal rat ventricular myocytes. The hypertrophic response of this model required interaction with extracellular matrix proteins. Specificity of these results was confirmed by demonstrating that ventricular myocytes plated onto an anti-beta1 integrin antibody supported the hypertrophic gene response. Adenovirus-mediated overexpression of beta1 integrin augmented the myocyte hypertrophic response when assessed by protein synthesis and atrial natriuretic factor production, a marker gene of hypertrophic induction. DNA synthesis was not altered by integrin overexpression. Transfection of cultured cardiac myocytes with either the ubiquitously expressed beta1A integrin or the cardiac/skeletal muscle-specific beta1 isoform (beta1D) activated reporter expression from both the atrial natriuretic factor and myosin light chain-2 ventricular promoters, genetic markers of ventricular cell hypertrophy. Finally, suppression of integrin signaling by overexpression of free beta1 integrin cytoplasmic domains inhibited the adrenergically mediated atrial natriuretic factor response. These findings show that integrin ligation and signaling are involved in the cardiac hypertrophic response pathway.

A genetic analysis of integrin function: Glanzmann thrombasthenia in vitro.

Glanzmann thrombasthenia, an inherited bleeding disorder, can be caused by a defect or deficiency in platelet integrin alphaIIb beta3 (GPIIb-IIIa). Studies of thrombasthenia variants have facilitated identification of sites involved in the functions of alphaIIb beta3 and other integrins. Such sites include those that bind ligand and those that participate in the "activation" of alphaIIb beta3 required for high affinity binding of ligands such as fibrinogen or PAC1, a monoclonal antibody. Here we describe the isolation of such variants, created in vitro with Chinese hamster ovary cells that express an activated form of alphaIIb beta3. These cells were exposed to a mutagen, ethyl methane sulfonate, and variants that lost the capacity to bind PAC1 were isolated by fluorescence-activated cell sorting. These variants were grouped into three phenotypic classes. One comprised integrin mutations that disrupt ligand binding function; a second comprised mutations that interfere with the capacity of cells to activate the integrin. Most of these activation-defective mutations were in the integrin cytoplasmic domain, but surprisingly, several were caused by mutations affecting three closely spaced residues in the beta3 extracellular domain. A third class of mutants exhibited a defect in integrin activation not ascribable to changes in the integrin sequence. Thus, these may represent mutated signaling molecules required for integrin activation. This unbiased genetic approach provides new insights into the structural basis of integrin function and may assist in identifying the cellular events that regulate integrin function.

Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness.

Migration of cells in higher organisms is mediated by adhesion receptors, such as integrins, that link the cell to extracellular-matrix ligands, transmitting forces and signals necessary for locomotion. Whether cells will migrate or not on a given substratum, and also their speed, depends on several variables related to integrin-ligand interactions, including ligand levels, integrin levels, and integrin-ligand binding affinities. These and other factors affect the way molecular systems integrate to effect and regulate cell migration. Here we show that changes in cell migration speed resulting from three separate variables-substratum ligand level, cell integrin expression level, and integrin-ligand binding affinity-are all quantitatively predictable through the changes they cause in a single unifying parameter: short-term cell-substratum adhesion strength. This finding is consistent with predictions of a mathematical model for cell migration. The ligand concentration promoting maximum migration speed decreases reciprocally as integrin expression increases. Increases in integrin-ligand affinity similarly result in maximal migration at reciprocally lower ligand concentrations. The maximum speed attainable, however, remains unchanged as ligand concentration, integrin expression, or integrin-ligand affinity vary, suggesting that integrin coupling with intracellular motors remains unaltered.

Ligand binding to integrin alphaIIbbeta3 is dependent on a MIDAS-like domain in the beta3 subunit.

Substitution of beta3 residue Asp119, Ser121, or Ser123 results in a loss of the ligand binding function of integrin alphaIIbbeta3. Homologous residues in other integrin beta subunits are similarly critical for ligand binding function. This DXSXS motif is also present in the I domain of certain integrin alpha subunits, where it constitutes a portion of the unique metal ion-dependent adhesion site (MIDAS). In this report, we have utilized the crystal structure of the recombinant alphaM I domain to produce a three-dimensional model of the homologous region in the integrin beta3 subunit. We performed mutagenesis of candidate amino acid residues predicted from this model to be involved in cation coordination and ligand binding. We report the identification of Asp217 and Glu220 as residues essential for the ligand binding function of alphaIIbbeta3. Alanine substitution of these residues did not affect receptor expression but abolished the binding of activation-dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies. In our proposed model, beta3 Asp217 is analogous to a metal-coordinating residue in the alphaM MIDAS domain, while Glu220 does not correspond to a functional MIDAS domain residue. Substitution of the highly conserved beta3 residue Thr197 corresponding to a critical MIDAS metal-coordinating Thr residue did not affect ligand binding function, suggesting that this region of beta3 adopts a structure that is very similar to but not identical to that of the MIDAS domain. These data support a functional linkage between these two sequences and further define a common feature of ligand binding to integrins.

A molecular basis for affinity modulation of Fab ligand binding to integrin alphaIIb beta3.

The Arg-Gly-Asp (RGD) sequence within the third complementarity-determining region (CDR3) of the heavy chain (H3) is responsible for the binding of the recombinant murine Fab molecules, AP7 and PAC1.1, to the platelet integrin alphaIIbbeta3. AP7 binding is minimally influenced by the conformational state of this receptor, whereas PAC1.1 binds preferentially to the activated state of the receptor induced by platelet agonists. To study the molecular basis for this functional difference, we replaced the AP7 H3 loop (HPFYRGDGGN) with all or segments of the analogous sequence from PAC1.1 (RSPSYYRGDGAGP). AP7 Fd (VH domain + Cgamma1 domain) segments containing these H3 loop sequences were expressed as active Fab molecules by coinfection of Spodoptera frugiperda cell lines with recombinant baculoviruses containing Fd and AP7 kappa chain cDNA. Replacement of the entire AP7 H3 loop with that from PAC1.1 generated the mutant AP7.3 Fab molecule, which bound selectively to either activated, gel-filtered platelets or to purified alphaIIbbeta3 in a manner identical to that of PAC1.1. Identical results were obtained when solely the sequences flanking the amino side of RGD within the respective H3 loops were exchanged. AP7.3 and PAC1.1 exhibited saturable but submaximal binding to activated gel-filtered platelets. Relative to AP7, the number of AP7.3 or PAC1. 1 Fab molecules bound per platelet was 17% in the presence of 1 m Ca2+ + 1 mM Mg2+ or 40% in the presence of 10 microM Mn2+. The ratio of Fab molecules bound after versus before activation (mean =/- S.D.; n = 3) was: for AP7.3, 9.8 =/- 0.6; for PAC1.1, 8.8 +/- 0.3; and for AP7, 1.4 =/- 0.2. In addition, AP7 bound to the stably expressed integrin mutant alphaIIbbeta3(S123A), whereas AP7.3 and PAC1 did not. Because AP7.3 behaves in every respect like PAC1.1, we conclude that the ability of RGD-based ligands to distinguish activated from resting conformations of the integrin alphaIIbbeta3 can be regulated by limited amino acid sequences immediately adjacent to the RGD tripeptide. Furthermore, those Fab molecules that exhibit increased selectivity for the activated conformation of alphaIIbbeta3 bind to a subpopulation of this integrin on platelets that is modulated by divalent cations.

The amino-terminal one-third of alpha IIb defines the ligand recognition specificity of integrin alpha IIb beta 3.

The integrin alpha subunits play a major role in the regulation of ligand binding specificity. To gain further insight into the regions of the alpha subunits that regulate ligand specificity, we have utilized alpha v / alpha IIb chimeras to identify regions of alpha IIb that when substituted for the homologous regions of alpha v switched the ligand binding phenotype of alpha v beta 3 to that of alpha IIb beta 3. We report that the ligand recognition specificity of beta 3 integrins is regulated by the amino-terminal one-third of the alpha subunit. Substitution of the amino-terminal portion of alpha v with the corresponding 334 residues of alpha IIb reconstituted reactivity with both alpha IIb beta 3-specific activation-dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies in addition to small highly specific activation-independent ligands. In contrast, substitution of the amino-terminal portion alone or the divalent cation repeats alone were not sufficient to change ligand binding specificity. These data in combination with previous studies demonstrate that integrin ligand recognition requires cooperation between elements in both the alpha and beta subunits and indicate that the ligand binding pocket is a structure assembled from elements of both the alpha and beta subunits.

Ligand binding and affinity modulation of integrins.

Integrins are cell adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. The extracellular domains of these receptors possess binding sites for a diverse range of protein ligands. Ligand binding is divalent cation dependent and involves well-defined motifs in the ligand. Integrins can dynamically regulate their affinity for ligands (inside-out signaling). This ability to rapidly modulate their affinity state is key to their involvement in such processes as cell migration and platelet aggregation. This review will focus on two aspects of integrin function: first, on the molecular basis of ligand-integrin interactions and, second, on the underlying mechanisms controlling the affinity state of integrins for their ligands.

Platelet adhesion receptors.

The response to vascular injury involves attachment and aggregation of platelets, coupled with initiation of the coagulation cascade. These inter-related processes ensure that the vessel injury is rapidly blocked with an aggregated clump of platelets that is then stabilized by a crosslinked fibrin matrix. Initial adherence relies on the ability of the platelet adhesion receptors to bind subendothelial matrix molecules. Platelet activation then results in the expression of high affinity integrin receptors on the cell surface that bind soluble ligands, allowing platelets to aggregate and form a haemostatic plug.