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Paxillin: a Focal Adhesion-Associated Adaptor Protein

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Paxillin: a Focal Adhesion-Associated Adaptor Protein Oncogene (2001) 20, 6459 ± 6472 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Paxillin: a focal adhesion-associated adaptor protein Michael D Schaller*,1 1Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center and Comprehensive Center for In¯ammatory Disorders, University of North Carolina, Chapel Hill, North Carolina, NC 27599, USA Paxillin is a focal adhesion-associated, phosphotyrosine- The molecular cloning of paxillin revealed a number containing protein that may play a role in several of motifs that are now known to function in mediating signaling pathways. Paxillin contains a number of motifs protein ± protein interactions (see Figure 1) (Turner that mediate protein ± protein interactions, including LD and Miller, 1994; Salgia et al., 1995a). The N-terminal motifs, LIM domains, an SH3 domain-binding site and half of paxillin contains a proline-rich region that SH2 domain-binding sites. These motifs serve as docking could serve as an SH3 domain-binding site. Several sites for cytoskeletal proteins, tyrosine kinases, serine/ tyrosine residues conforming to SH2 domain binding threonine kinases, GTPase activating proteins and other sites were also noted. In addition, the N-terminal adaptor proteins that recruit additional enzymes into domain of paxillin contains ®ve copies of a peptide complex with paxillin. Thus paxillin itself serves as a sequence, called the LD motif, which are now known docking protein to recruit signaling molecules to a to function as binding sites for other proteins (see speci®c cellular compartment, the focal adhesions, and/ Table 1) (Brown et al., 1998a). The C-terminal half of or to recruit speci®c combinations of signaling molecules paxillin is comprised of four LIM domains, which are into a complex to coordinate downstream signaling. The zinc-binding structures resembling a double zinc ®nger biological function of paxillin coordinated signaling is domain. These domains were ®rst identi®ed in three likely to regulate cell spreading and motility. Oncogene transcription factors, lin-11, isl-1, mec-3. LIM domains (2001) 20, 6459 ± 6472. can also function to mediate protein-protein interac- tions (Dawid et al., 1998). The focal adhesion targeting Keywords: paxillin; integrin signaling; phosphotyro- sequence of paxillin is located in the C-terminal half of sine; cytoskeleton; cell motility; FAK the protein. The 3rd LIM domain plays a major role in targeting paxillin to focal adhesions, whereas LIM domain 2 plays a minor role (Brown et al., 1996). Paxillin was ®rst identi®ed as a 68 ± 70 kDa phospho- Presumably these LIM domains engage binding tyrosine-containing protein in cells transformed by the partners to direct and/or tether paxillin in focal src oncogene (Glenney Jr and Zokas, 1989). Further adhesions, but these binding partners have thus far characterization of the protein revealed that paxillin eluded identi®cation. Since paxillin does not exhibit localized to discrete structures in the cell called focal enzyme activity, but contains an array of docking sites adhesions, which are sites of close cellular contact for other proteins, it is believed to function as an with the underlying extracellular matrix (Turner et al., adaptor protein that facilitates the assembly of multi- 1990). Tyrosine phosphorylation of paxillin was protein complexes to coordinate signaling. observed following integrin-dependent cell adhesion to extracellular matrix proteins, thus implicating paxillin in integrin-mediated signaling (Burridge et Paxillin: alternative splicing and related proteins al., 1992). These early ®ndings generated a great deal of interest in paxillin providing the impetus for The ®rst paxillin isoform isolated, referred to as extensive analysis of the protein. These studies have paxillin a, is broadly expressed. Two alternatively provided us with our current vision of paxillin, a spliced variants of paxillin, paxillin b and paxillin g, focal adhesion-associated signaling molecule that have been described (Mazaki et al., 1997). Both of functions as an adaptor protein to recruit diverse these isoforms contain a short exon inserted just cytoskeleton and signaling proteins into a complex, downstream of LD motif 4, between lysine residue presumably to coordinate the transmission of down- 277 and phenylalanine residue 278 of paxillin a. stream signals. Paxillin b contains a 34 amino acid insertion and paxillin g contains a 48 residue insertion that is unrelated in sequence to the paxillin b speci®c exon. The expression pattern of paxillin b and paxillin g is *Correspondence: MD Schaller, Department of Cell and more restricted than the expression of paxillin a Developmental Biology, 534 Taylor Hall, CB 7090, University of North Carolina, Chapel Hill, North Carolina, NC 27599; (Mazaki et al., 1997). In fact, paxillin g may be a E-mail: [email protected] human speci®c isoform since the murine paxillin gene Paxillin: a focal adhesion-associated adaptor protein MD Schaller 6460 lacks the exon encoding the g-speci®c isoform originally isolated from a screen for TGF-b and sequences (Mazaki et al., 1998). Interestingly, the hydrogen peroxide inducible genes (Shibanuma et al., insertions appear to alter the ability of these paxillin 1994). Hic-5 is 57% identical to paxillin and contains isoforms to interact with other proteins (Mazaki et al., an organization of N-terminal LD motifs and C- 1997). Compared to paxillin a, paxillin b exhibits terminal LIM domains similar to paxillin. Hic-5 reduced binding to vinculin in vitro, but equivalent localizes to focal adhesions and shares a number of binding to FAK. In contrast, paxillin g is defective for binding partners with paxillin including FAK (Hag- FAK binding in vitro but retains vinculin-binding mann et al., 1998; Thomas et al., 1999a; Ishino et al., activity. It is not clear why these isoforms exhibit 2000a). The leupaxin cDNA was originally isolated altered binding to FAK and vinculin since the from a macrophage library and its expression in insertions do not appear to disrupt the LD4 motif, which is a FAK/vinculin binding site (see below). Further, both FAK and vinculin can bind to other LD motifs in the N-terminus of paxillin (see below), which are distant from the isoform speci®c insertions. Perhaps the insertions disrupt interactions with other binding partners that stabilize the association of FAK or vinculin with paxillin. Alternatively, these insertions may alter the conformation of the protein masking recognition of both the LD2 and LD4 motifs by FAK or vinculin. Paxillin is the founding member of a family of related proteins that now contains three members, paxillin, hic-5 and leupaxin (see Figure 2). Hic-5 was Figure 2 The paxillin family of proteins. A schematic illustra- tion comparing paxillin with hic-5 and leupaxin is shown. The proline-rich region is indicated as a black oval and LD motifs as white ovals. The location of alternatively splice exon insertions within paxillin is indicated. The LD motifs of hic-5 and leupaxin are designated 1, 2, 4 or 5 in this Figure to re¯ect sequence homology between the hic-5 or leupaxin LD motifs and speci®c Figure 1 Diagram of paxillin. The ®ve LD motifs in the N- LD motifs in paxillin. Note that the second LD motif of leupaxin terminal half of paxillin and the four C-terminal LIM domains is not highly related to any of the paxillin LD motifs and the N- are diagrammed. The proline-rich sequence and sites of tyrosine terminal LD motif of hic-5 (*) is present in the murine hic-5 phosphorylation within the N-terminal domain of paxillin are sequence but not the human hic-5 sequence. The per cent identity indicated. Sites of serine/threonine phosphorylation and the major between dierent regions of hic-5 or leupaxin and the focal adhesion targeting sequence of paxillin are also shown corresponding regions of paxillin are indicated Table 1 Alignment of LD motifs Paxillin LD1: M D D LDA LLADL ES Paxillin LD2: L S E LDR LLLEL NA Paxillin LD3: E S L LDE L ESSVPS Paxillin LD4: T R E LDE L MAS L SD Paxillin LD5: G S Q LDSML GS L QS Dmpax LD2: L S E LDS LLQDL QK Dmpax LD4: T K E LDD L MAS L SD Dmpax LD5: E D Q LDSML GNL QA Hic-5 LD1: M E D LDA LLSDL ET Hic-5 LD2: L C E LDR LLQEL NA Hic-5 LD3: T Q E LDR L MAS L SD Hic-5 LD4: K G S LDTML GL L QS Leupaxin LD1: M E E LDA LLEEL ER Leupaxin LD2: E T N LDET S EI L ST Leupaxin LD3: A A Q LDE L MAHL TE Leupaxin LD4: K A S LDSML GGL EQ The LD motifs from the human paxillin (Salgia et al., 1995a), murine hic-5 (Thomas et al., 1999a), Drosophila paxillin (Dmpax) (Wheeler and Hynes, 2001) and leupaxin (Lipsky et al., 1998). Note that Drosophila paxillin does not contain a conserved LD1 or LD3 and that the leupaxin LD2 motif is not conserved in paxillin. Both hic-5 and leupaxin contain only four LD domains. Highly conserved leucine and aspartic acid residues within the LD motif are highlighted in bold Oncogene Paxillin: a focal adhesion-associated adaptor protein MD Schaller 6461 lymphoid tissue documented (Lipsky et al., 1998). tidylinositol-bisphosphate (Gilmore and Burridge, Leupaxin exhibits 37% identity with paxillin and 1996). Vinculin may function to connect the actin contains the same domain organization as paxillin cytoskeleton to paxillin. with N-terminal LD motifs and four C-terminal LIM domains (Lipsky et al., 1998). As expected from the Actopaxin Actopaxin is a 42-kDa protein that binds sequence conservation, leupaxin can associate with a LD1 and LD4 of paxillin (Nikolopoulos and Turner, number of the same proteins that can bind paxillin 2000).
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