Recombinant human DKK-1 protein (Qk068)

Protein background

Dickkopf-related protein 1 (DKK-1) is a protein integral to the regulation of the Wnt signaling pathway and plays a pivotal role in embryonic development, tissue homeostasis, and various pathological conditions, including cancer [1-4]. As a member of the DKK protein family alongside DKK-2, DKK-3, and DKK-4, DKK-1 was initially identified as a Xenopus head-forming molecule and functions as a potent antagonist of the Wnt signaling pathway  [1].

With cell culture application, DKK1 is widely used for orchestrating cell fate decisions, self-renewal, and differentiation [5-6]. Its addition to the cell culture medium facilitates the binding to LDL receptor-related proteins 5 and 6 (LRP5/6) co-receptors, thereby inhibiting the activation of the canonical Wnt/β-catenin pathway  [7-8]. This interference proves instrumental in maintaining pluripotency, particularly by finely regulating the equilibrium between self-renewal and differentiation in embryonic stem cells (ESCs) [9].

The versatile utility of DKK-1 extends to the directed differentiation of induced pluripotent stem cells (iPSCs) into specific lineages, including neural differentiation, where it serves to promote the development of neural lineages [10]. Additionally, DKK-1 guides osteogenic differentiation of mesenchymal stem cells (MSCs), offering implications for bone tissue engineering and other related applications [11].

In the context of disease modeling in vitro, DKK1 finds application in mimicking conditions associated with dysregulated Wnt signaling pathways, as seen in certain cancers exhibiting aberrant Wnt expression, such as esophageal squamous cell carcinomas and hormone-resistant breast cancers [12].

Further insights into the regulatory mechanisms of DKK1 and its familial counterpart DKK-4 underscore their significant roles in modulating the Wnt/β-catenin signaling pathway. This pathway involves the interaction of Wnt ligands with the seven-transmembrane receptor Frizzled, along with co-receptors LRP5 and LRP6. DKK-1 forms inhibitory complexes with LRP5 and LRP6, as well as another receptor, Kremen, leading to endocytosis of this complex and subsequent removal of LRP5 and LRP6 from the cell surface [13-14].

DKK1 protein exhibits a structured composition. It includes an N-terminal signal peptide directing its secretion, a conserved cysteine-rich domain (CRD) crucial for disulfide bond formation, and a linker connecting the CRD to the C-terminal region. This C-terminal region interacts with other proteins and is implicated in the overall conformation and function of DKK-1. Specific amino acid residues within the CRD and C-terminal regions are vital for DKK-1’s inhibitory effect on the Wnt signaling pathway [15].

Notably, DKK-1’s inhibition of the Wnt pathway proves indispensable for anterior development, disrupting posterior patterning in vertebrates. This is evident in mice lacking DKK1 expression, where a deficiency leads to the absence of head formation [2,16]. Collectively, these molecular and functional insights underscore DKK-1’s intricate role in cellular processes and its potential as a valuable tool in manipulating cellular behavior in diverse experimental settings.