The SH3PXD2A gene is located on chromosome 10 (10q24.33). It contains 15 exons.

The full-length SH3PXD2A transcript is 11264 nt in length. Multiple TKS5 isoforms arise as a result of alternative mRNA splicing involving exons 7 and 10, and alternative use of transcription start sites.

The full-length SH3PXD2A transcript (TKS5-LONG or TKS5-ALPHA) is transcribed from a promoter upstream of exon 1 and is translated into a 150 kDa protein that contains a Phox-homology (PX) domain in the N-terminus and five Src homology 3 (SH3) domains in the C-terminus. The shorter isoforms that arise from downstream transcription start sites lack the PX domain but retain the five SH3 domains. Because the PX domain is required for binding to the cell membrane, full-length TKS5 is able to localize to invadosome foci but the short isoforms cannot.

TKS5 expression is detected in many tissue types, including brain, lung, liver, heart, skeletal muscles, and, kidneys, but was low in spleen and absent in testis (Lock et al, 1998). Tks5 has also been detected in many cell types, including macrophages, myoblasts, neural crest cells, osteoblasts, and neurons (Burger et al., 2011; Thompson et al., 2008; Murphy et al., 2011; Oikawa et al., 2012; Santiago-Medina et al. 2015).

Cytoplasmic and at invadosome foci.

TKS5 was initially identified as a substrate for SRC (Lock et al., 1998), and was subsequently shown to play a critical role in invadosome formation in multiple cell types (Courtneidge, 2011; Murphy and Courtneidge, 2011; Paz et al., 2013).
Full-length TKS5 functions as an adaptor for recruiting other proteins to the cell membrane for invadosome formation. The recruitment of TKS5 to the cell membrane depends on its PX domain and phosphorylation by Src (Abram et al., 2003). It has been proposed that phosphorylation of TKS5 releases its PX domain from intramolecular interaction and allows TKS5 to bind to cell membrane phosphatidylinositol lipids, such as phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) (Abram et al., 2003; Oikawa et al., 2008). At the cell membrane, TKS5 is thought to interact with multiple components of invadosomes either directly or indirectly, and thereby mediates invadosome formation and maturation (Sharma et al., 2013). These interacting partners includes adaptor proteins and actin regulatory proteins, such as NCK1, NCK2, GRB2, CTTN (Cortactin), WASL (N-WASP), ACTR2/ACTR3 (Arp2/3) complex, and ARHGAP35 (p190RhoGAP) (Crimaldi et al., 2009; Oikawa et al., 2008; Stylli et al., 2009).
TKS5 also interacts with NOXA1 and CYBA (p22phox), which are components of the NADPH oxidase complex, and thereby promotes reactive oxygen species (ROS) production by NOX enzymes at invadosomes (Diaz et al., 2009; Gianni et al., 2010; 2009). ROS have been shown to facilitate invadosome formation by maintaining or amplifying the phosphorylation of TKS5. As such, TKS5 is thought to promote invadosome formation via ROS in a positive feedback loop.
Finally, TKS5 has also been shown to interact with members of the ADAM family metalloproteases, specifically ADAM12, ADAM15, ADAM19 (Abram et al., 2003). It is believed that Tks5 recruits theses proteases to the invadosome foci for processing growth factors and regulating cell motility. For example, ADAM12 has been shown to promote ectodomain shedding of HBEGF (heparin-binding EGF-like growth factor) and enhance invadopodia formation in cancer cells (Diaz et al., 2013).
In the context of cancer, TKS5-dependent formation of invadopodia is thought to promote metastasis by mediating local tumor invasion and intravasation at the primary site, as well as extravasation and colonization at the distant site (Murphy and Courtneidge, 2011; Paz et al., 2014). In the context of normal development, TKS5-depedent podosomes are important for mediating cell migration during embryogenesis. Knockdown of Tks5 in zebrafish led to impaired dorsal-ventral migration of neural crest cells and defective craniofacial structures and pigmentation (Murphy et al., 2011). Similarly, genetic deletion of Tks5 in mice led to complete cleft of the secondary palate and neonatal death (Cejudo-Martin et al., 2014). In addition, study in Xenopus showed that Tks5-dependent podosomes are also required for the migration of neuronal growth cones (Santiago-Medina et al., 2015).
While most studies have focused on full-length TKS5, shorter isoforms of TKS5 that lack the PX domain have been reported (Lock et al, 1998; Li et al., 2013; Cejudo-Martin et al., 2014). There are few reports on the functions of these short isoforms. Experiments in mouse lung cancer cell lines showed that overexpression of a short isoform (Tks5-short) suppressed invadopodia function by disrupting the stability of invadopodia (Li et al., 2013). In addition, overexpression of a short-form equivalent protein, ΔPX-Tks5, in Xenopus neural crest cells inhibited invadosome functions and impaired motoneuron axon extension into the peripheral myotomal tissue in Xenopus embryos (Santiago-Medina et al., 2015). These data suggest that the short forms of TKS5 can function as negative regulators of invadosomes.
At the mRNA level, the transcription of full-length Tks5 has been shown to be synergistically inhibited by the developmental regulators NKX2-1, FOXA2, and CDX2 in lung adenocarcinoma (Li et al., 2015). Furthermore, TKS5 has been shown to be a target of the microRNA mir200-c (Sundararajan et al., 2015). In terms of protein stability and abundance, the full-length isoform of TKS5 is positively regulated by Src, while the short isoform (TKS5-beta) is negatively regulated by Src (Cejudo-Martin et al. 2014).

TKS5 is homologous to SH3PXD2B (TKS4), another adaptor protein that functions as a Src substrate and promotes invadosome function (Buschman et al, 2009). TKS4 contains a PX domain at the N-terminus and four SH3 domains in the C-terminus.