Review Cortactin: Cell Functions of A Multifaceted Actin-Binding Protein Michael Schnoor, 1, * Theresia E. Stradal, 2,4 and Klemens Rottner 2,3,4 Cortactin fulfills many functions in various cell types. These functions have been considered to derive from its ability to activate the Actin-related protein 2/3 (Arp2/3) complex, and are regulated by post-translational modifications, including phosphorylation and acetylation. New evidence suggests that cor- tactin regulates cell migration by controlling the deposition of extracellular matrix proteins rather than lamellipodial Arp2/3 activation, and that cortactin also functions in GTPase signaling, vesicular trafficking, and actomyosin con- tractility. These recent new findings and concepts are relevant for physiological and pathological cell functions, but have not yet been put into mechanistic context. Here, we reconsider current thinking on cortactin functions in different cell types during health and disease, and discuss potential directions of future research in cortactin biology. Cortactin: A Versatile Actin-Binding Protein Originally discovered as an 80/85-kDa substrate of Src kinase during the early 1990s [1], cortactin was rapidly recognized as an actin-binding protein (ABP) targeting actin structures at the cell cortex, hence its name. Cortactin accumulates in actin-rich lamellipodia (see Glossary) and membrane ruffles formed at the migrating front of cells or, for example, during pathogen entry (Box 1) [2,3]. Lamellipodia are thin sheets of plasma membrane filled with actin filaments that protrude in the direction of migration effected by actin polymerization. When lifting up- and backwards from planar substrata or forming at apical cell surfaces as 3D structures, lamelli- podia are generally referred to as ‘ruffles’, although the molecular mechanisms driving their formation are considered to be the same [4]. Lamellipodial actin filament networks and membrane ruffles are built by the branching activity of the Arp2/3 complex [5]. This seven-subunit protein complex is intimately related to cortactin biology (see below). The Arp2/3 complex is obligatory for the formation of branched actin networks not only in lamellipodia and ruffles, but also at sites of endocytosis, exocytosis, trafficking vesicles, cell–cell or cell–substrate adhesions, [653_TD$DIFF]such as podosomes of hematopoietic cells and their analogs in tumor cells (invadopodia) [6–8]. Notably, all of these structures have been described to accumulate cortactin [9,10]. However, its subcellular distribution does not entirely mirror that of the Arp2/3 complex, because actin filaments embedded into lamellipodia, termed ‘micro- spikes’, are enriched in cortactin, but lack the Arp2/3 complex [11]. The cortactin variants expressed in humans are encoded by two genes, the CTTN gene (formerly called EMS1)(Figure 1) giving rise to the ubiquitously expressed cortactin and its variants (see below), and the hematopoietic cell-specific Lyn substrate 1 (HCLS1) or HS1 gene (Box 2) [12]. Key features of cortactin and HS1 comprise an N-terminal acidic domain con- taining a tryptophan at position 22 (21 in HS1) critical for interactions with the Arp2/3 complex, Trends Actin filament assembly and Arp2/3 complex activation driving lamellipodia protrusion require the WAVE complex but not cortactin. Cortactin regulates cell migration through regulation of extracellular matrix protein secretion and activation of Rho-GTPases. Cortactin contributes to the regulation of other important cellular processes, such as vesicular trafficking, exocyto- sis, GTPase signaling, and transcrip- tional regulation. In contrast to common thinking, expression of cortactin has now been reported in many hematopoietic cells. Aside from cancer, cortactin is involved in many other diseases[652_TD$DIFF]. 1 Department of Molecular Biomedicine, CINVESTAV-IPN, 07360 Mexico-City, Mexico 2 Department of Cell Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany 3 Division of Molecular Cell Biology, Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany 4 These authors contributed equally *Correspondence: mschnoor@cinvestav.mx (M. Schnoor). TICB 1382 No. of Pages 20 Trends in Cell Biology, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.tcb.2017.10.009 1 © 2017 Elsevier Ltd. All rights reserved.