Paks4, along with Paks5, and 6 are members of the group B family of p21-activated kinases (Paks). The Paks play multiple different roles in controlling cell morphology, cell growth, proliferation, and signaling. Pak4 has essential roles in embryonic development (Qu et al., 2003), but in adults high levels of Pak4 are frequently associated with cancer. Pak4 has been implicated in several types of cancer (Wells and Jones, 2010; Eswaran et al., 2009; Liu et al., 2008; and Liu et al., 2010) and it is strongly linked to breast cancer (Liu et al., 2008; Liu et al. 2010; Yu et al., 2009; Rafn et al., 2012; and So et al., 2012). Breast tumors and breast cancer cell lines frequently have high levels of Pak4 (Liu et al., 2008), and overexpression of Pak4 in mammary epithelial cells leads to tumorigenesis in mice (Liu et al., 2010). This paper summarizes the current work on the role of Pak4 in breast cancer. 1. Introduction The p21-activated kinase (PAK) family of serine/threonine kinases have important roles in cytoskeletal organization, cell signaling, and cell proliferation and survival [1, 2]. They were first identified as effector proteins for Cdc42 and Rac, members of the Rho GTPase family, but they can respond to many different types of signals. The Paks fall into two categories, group A and group B, based on their sequences and functions (see Figure 1). Figure 1: Schematic diagram of the structures of the group A and group B Pak family members. The group A and group B Paks share in common an amino terminal GTPase binding domain (GBD) and a carboxyl terminal serine/threonine kinase domain, as illustrated in Figure 1. The GBD and kinase domains of the two groups, however, have only approximately 50% identity with each other, and the regulatory domains outside of the GBD and kinase domains are completely different in the group B Paks compared with the group A Paks. The different Paks also differ in their substrate specificity, although there is also some overlap [3, 4]. The different Pak family members differ in their expression patterns. Pak4 expression is high throughout the embryo during the development, but in many adult tissues Pak4 protein levels are low. Pak4 has an important role in embryonic development [5], but in adult tissues Pak4 overexpression is often associated with cancer. This paper will focus on Pak4, and recent studies aimed at investigating its role in breast cancer. 2. Pak4 and Breast Cancer Numerous studies point to a role for the Pak kinases in oncogenic transformation [6–15]. Among the group B Paks, Pak4 is most closely linked to
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