DDR1

Official Full Name

discoidin domain receptor tyrosine kinase 1

Organism

Homo sapiens

GeneID

780

Background

Receptor tyrosine kinases play a key role in the communication of cells with their microenvironment. These kinases are involved in the regulation of cell growth, differentiation and metabolism. The protein encoded by this gene belongs to a subfamily of tyrosine kinase receptors with homology to Dictyostelium discoideum protein discoidin I in their extracellular domain, and that are activated by various types of collagen. Expression of this protein is restricted to epithelial cells, particularly in the kidney, lung, gastrointestinal tract, and brain. In addition, it has been shown to be significantly overexpressed in several human tumors. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

Synonyms

CAK; DDR; NEP; HGK2; PTK3; RTK6; TRKE; CD167; EDDR1; MCK10; NTRK4; PTK3A;

Bio Chemical Class

Kinase

Protein Sequence

MGPEALSSLLLLLLVASGDADMKGHFDPAKCRYALGMQDRTIPDSDISASSSWSDSTAARHSRLESSDGDGAWCPAGSVFPKEEEYLQVDLQRLHLVALVGTQGRHAGGLGKEFSRSYRLRYSRDGRRWMGWKDRWGQEVISGNEDPEGVVLKDLGPPMVARLVRFYPRADRVMSVCLRVELYGCLWRDGLLSYTAPVGQTMYLSEAVYLNDSTYDGHTVGGLQYGGLGQLADGVVGLDDFRKSQELRVWPGYDYVGWSNHSFSSGYVEMEFEFDRLRAFQAMQVHCNNMHTLGARLPGGVECRFRRGPAMAWEGEPMRHNLGGNLGDPRARAVSVPLGGRVARFLQCRFLFAGPWLLFSEISFISDVVNNSSPALGGTFPPAPWWPPGPPPTNFSSLELEPRGQQPVAKAEGSPTAILIGCLVAIILLLLLIIALMLWRLHWRRLLSKAERRVLEEELTVHLSVPGDTILINNRPGPREPPPYQEPRPRGNPPHSAPCVPNGSALLLSNPAYRLLLATYARPPRGPGPPTPAWAKPTNTQAYSGDYMEPEKPGAPLLPPPPQNSVPHYAEADIVTLQGVTGGNTYAVPALPPGAVGDGPPRVDFPRSRLRFKEKLGEGQFGEVHLCEVDSPQDLVSLDFPLNVRKGHPLLVAVKILRPDATKNARNDFLKEVKIMSRLKDPNIIRLLGVCVQDDPLCMITDYMENGDLNQFLSAHQLEDKAAEGAPGDGQAAQGPTISYPMLLHVAAQIASGMRYLATLNFVHRDLATRNCLVGENFTIKIADFGMSRNLYAGDYYRVQGRAVLPIRWMAWECILMGKFTTASDVWAFGVTLWEVLMLCRAQPFGQLTDEQVIENAGEFFRDQGRQVYLSRPPACPQGLYELMLRCWSRESEQRPPFSQLHRFLAEDALNTV

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Detailed Information

DDR1 (Discoidin Domain Receptor Tyrosine Kinase 1) is a receptor tyrosine kinase that belongs to the DDR (Discoidin Domain Receptor) family. It is widely expressed in various tissues and plays a crucial role in regulating cell proliferation, migration, and differentiation. This article aims to provide an overview of DDR1 gene structure, function, and its implications in various physiological and pathological processes.

Gene Structure of DDR1

The DDR1 gene is located on chromosome 6p21.3 and spans approximately 100 kb. It consists of 21 exons and encodes a protein of approximately 140 kDa. The encoded protein contains a signal peptide, a discoidin domain, a tyrosine kinase domain, and a carboxy-terminal tail. The discoidin domain is responsible for ligand binding, while the tyrosine kinase domain is involved in intracellular signaling.

Function of DDR1

DDR1 functions as a cell surface receptor that binds to various extracellular matrix proteins, including collagen, fibronectin, and laminin. Upon ligand binding, DDR1 undergoes dimerization and autophosphorylation, leading to the activation of downstream signaling pathways. Some of the major signaling pathways regulated by DDR1 include the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, and the Src family kinase pathway.

Fig1. DDR1-ECD (blue oval)-remodelled collagen fibres (red curvy lines) forming an immune-excluding barrier. The intracellular region of DDR1 (yellow ovals) triggers downstream signal transduction.

Role in Cell Proliferation of DDR1

DDR1 promotes cell proliferation by regulating the MAPK pathway, which is essential for cell growth and division. Activated DDR1 phosphorylates and activates Raf, a component of the MAPK pathway, leading to the subsequent activation of MEK and ERK. ERK phosphorylates various substrates, including cyclin D1, cyclin E, and Rb, promoting cell cycle progression.

Role in Cell Migration of DDR1

DDR1 also plays a critical role in cell migration by regulating the PI3K pathway. Upon DDR1 activation, PI3K is recruited to the plasma membrane and phosphorylates PIP2, generating PIP3. PIP3 binds to the pleckstrin homology domain of AKT, promoting its activation. AKT phosphorylates various substrates, including GSK3β and paxillin, which are involved in cytoskeletal rearrangement and cell migration.

Role in Cell Differentiation of DDR1

In addition to promoting cell proliferation and migration, DDR1 also plays a role in cell differentiation. It has been shown that DDR1 activation promotes the differentiation of various cell types, including osteoblasts, chondrocytes, and fibroblasts. This is achieved by regulating the expression of specific transcription factors, such as Runx2 and Sox9, which are essential for cell differentiation.

Pathological Implications of DDR1

DDR1 has been implicated in various pathological processes, including cancer, fibrosis, and inflammation. In cancer, DDR1 is often overexpressed and promotes tumor growth, invasion, and metastasis. DDR1 activation has also been linked to the development of fibrosis, a condition characterized by excessive collagen deposition and tissue scarring. Inflammation, another pathological condition, is also regulated by DDR1, as it modulates the recruitment and activation of immune cells.

In conclusion, DDR1 is a versatile regulator of cell signaling that plays a crucial role in cell proliferation, migration, and differentiation. Its involvement in various physiological and pathological processes highlights the importance of understanding its function and mechanism.

References:

Su, Hua et al. "Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome." Nature vol. 610,7931 (2022): 366-372. doi:10.1038/s41586-022-05169-z
Sun, Xiujie et al. "Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion." Nature vol. 599,7886 (2021): 673-678. doi:10.1038/s41586-021-04057-2

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