A meta-analysis indicates that the regulation of cell motility is a non-intrinsic function of chemoattractant receptors that is governed independently of directional sensing

Abstract

Chemoattraction, defined as the migration of a cell toward a source of a chemical gradient, is controlled by chemoattractant receptors. Chemoattraction involves two basic activities, namely, directional sensing, a molecular mechanism that detects the direction of a source of chemoattractant, and actin-based motility, which allows the migration of a cell towards it. Current models assume first, that chemoattractant receptors govern both directional sensing and motility (most commonly inducing an increase in the migratory speed of the cells, i.e. chemokinesis), and, second, that the signaling pathways controlling both activities are intertwined. We performed a meta-analysis to reassess these two points. From this study emerge two main findings. First, although many chemoattractant receptors govern directional sensing, there are also receptors that do not regulate cell motility, suggesting that is the ability to control directional sensing, not motility, that best defines a chemoattractant receptor. Second, multiple experimental data suggest that receptor-controlled directional sensing and motility can be controlled independently. We hypothesize that this independence may be based on the existence of separated signalling modules that selectively govern directional sensing and motility in chemotactic cells. Together, the information gathered can be useful to update current models representing the signalling from chemoattractant receptors. The new models may facilitate the development of strategies for a more effective pharmacological modulation of chemoattractant receptor-controlled chemoattraction in health and disease.

Keywords: actin; chemoattractant; chemoattractant receptor; chemoattraction; chemotaxis; directional sensing; migration; motility.

Figure 1

Signaling pathways controlling actin dynamics downstream of the Rho family of small GTPases Black and red lines indicate stimulatory and inhibitory effects, respectively. Dashed black or red lines indicate that upon inhibition of a specific molecule, ceases the stimulatory or inhibitory effect exerted by this molecule on its direct downstream target. In the lower part of the figure is indicated the effect of the indicated pathway on F-actin. Abbreviations: Arp2/3, Actin Related Protein 2/3 complex; CaM, Calmodulin; Cdc42, Cell Division Cycle 42; GAP, GTPase-activating proteins; GDP, Guanosine diphosphate; GEF, Guanine nucleotide exchange factors; GTP, Guanosine-5’-triphosphate; LIMK, LIM Motif-Containing Protein Kinase; mDia, mammalian Diaphanous-related formin; MLC, myosin light chain; MLCK, myosin light-chain kinase; MLCP, Myosin Light-Chain Phosphatase; PAK, p21-activated kinase; Rac, Ras-Related C3 Botulinum Toxin Substrate; RhoA, Ras homolog family member A; ROCK, Rho-associated protein kinase; SSH1, slingshot protein phosphatase 1; WASP, Wiskott-Aldrich Syndrome protein; WAVE, WASP-family verprolin-homologous protein.

Figure 2

The ability to control chemokinesis is not an obligatory activity of chemoattractant receptors Chemotaxis involves directional sensing and motility. Chemoattractant receptors can be functionally classified into two groups. (A) Receptors that control both directional sensing and motility (chemokinesis). (B) Receptors that control directional sensing, but not chemokinesis, implying that stimulation of these receptors do not alter the speed of the cells. Current models of chemoattractant receptors-mediated signaling are largely based on the receptors shown in (A) See Tables 1 , 2 , for examples of both types of receptors.

Figure 3

CCR7 uses highly independent signaling modules to regulate the functions of dendritic cells Working model based largely on our experimental data obtained studying the functions and signaling molecules controlling the functions of CCR7 in DCs. Black and red lines indicate stimulatory and inhibitory effects, respectively. A dashed black or red line indicates that after stimulation of CCR7, ceases the indicated effect, either activation or inhibition, exerted by the indicated molecule. An asterisk indicates molecules not analyzed experimentally by us, which are included based on bibliographic information. Endocytosis can be downstream of RhoA (green) and Rac/Cdc42 (orange). The dashed vertical rounded rectangle includes the signaling modules governing CCR7-induced actin dynamics and directional sensing. Signaling module governing CCR7-mediated directional sensing (mallow). Signalling module controlling CCR7-mediated actin dynamics (green). Signaling module controlling CCR7-mediated survival (yellow). Pro-apoptotic molecules that are inhibited by the survival regulatory module (flesh colour). Abbreviations used (see also legend to Figure 1 , for additional abbreviations): Akt, AK strain mouse Thymoma; AMPK; 5’ AMP-activated protein kinase; Bak, Bcl-2-antagonist/killer; Bax, Bcl-2-Associated X Protein; Bclxl, B-cell lymphoma-extra-large; Bim, Bcl-2 Interacting Mediator of cell death; Mst1, Mammalian sterile 20-like kinase 1; eIF4E, Eukaryotic translation initiation factor 4E; 4E-BP1, eIF4E-binding protein 1; FOXO1/3, Forkhead box O 1/3; GSK3β, glycogen synthase kinase-3β; JNK, c-Jun N-terminal kinase; p38, p38 mitogen-activated protein kinases; MEK1/2, MAPK/ERK Kinase 1 and 2; ERK1/2, extracellular signal-regulated kinase 1 and 2; mTORC1, mTORC2, mechanistic target of rapamycin complex 1 and 2; NFκB, Nuclear factor kappa-light-chain-enhancer of activated BC; PM, plasma membrane; Pyk2, Proline-rich tyrosine kinase 2; Raf, Rapidly accelerated fibrosarcoma kinase; S6, S6 protein; RheB; Ras homolog enriched in brain; S6K, S6 kinase; TSC2, Tuberous sclerosis complex 2.

Figure 4

CCR7 could use highly independent signaling modules to regulate directional sensing and migratory speed in T cells. Hypothetical model based on recently published data (see text for details). The signalling module controlling CCR7-mediated actin dynamics that governs cytoarchitecture and migratory speed is downstream of RhoA, which is regulated by Mst1/RapL/Rap1 (green). RapL/Rap1 also govern LFA-1 integrin activation. Signaling module governing CCR7-mediated directional sensing (mallow). Abbreviations (see legends to Figure 1 ; Tables 2 , 3 , for additional abbreviations): LFA-1 (αlβ2), Lymphocyte function-associated antigen-1; Rap 1, Ras-related protein 1; Rap L, Rap1-binding molecule, regulator of adhesion and cell polarization enriched in lymphoid tissues; Ras, Rat sarcoma viral oncogene homolog.