second cysteine-rich (Cys-2) domain of Dickkopf-related protein 4; Dickkopf 4 (Dkk4) is a secreted protein which directly binds to LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and is an inhibitor of Wnt/beta-catenin signaling. Dkk4, which is upregulated by the activated Wnt pathway, contributes to tumor malignancy in variable tumors, promoting tumor cell invasion and progression. Aberrant accumulation of Dkk4 has been shown to promote tumor progression by forming the immune suppressive microenvironment in gastrointestinal stromal tumor, and thus Dkk4 may be used as a tumor biomarker for prognosis prediction and recurrence monitoring. Dkk4 belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dkk4.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034659928 128 KPSIKKSQGRKGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTAQAPEIFQRCDCGPGLLCRSQLT 207
Cdd:cd23275     1 KPGIKKSQSSKGQEGESCLRTSDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTAQGPEIFQRCDCGPGLSCRSQLT 80

                          90
                  ....*....|....
gi 1034659928 208 SNRQHARLRVCQKI 221
Cdd:cd23275    81 GNRQHSRLRVCQRI 94

second cysteine-rich (Cys-2) domain of Dickkopf-related protein 4; Dickkopf 4 (Dkk4) is a secreted protein which directly binds to LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and is an inhibitor of Wnt/beta-catenin signaling. Dkk4, which is upregulated by the activated Wnt pathway, contributes to tumor malignancy in variable tumors, promoting tumor cell invasion and progression. Aberrant accumulation of Dkk4 has been shown to promote tumor progression by forming the immune suppressive microenvironment in gastrointestinal stromal tumor, and thus Dkk4 may be used as a tumor biomarker for prognosis prediction and recurrence monitoring. Dkk4 belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dkk4.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034659928 128 KPSIKKSQGRKGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTAQAPEIFQRCDCGPGLLCRSQLT 207
Cdd:cd23275     1 KPGIKKSQSSKGQEGESCLRTSDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTAQGPEIFQRCDCGPGLSCRSQLT 80

                          90
                  ....*....|....
gi 1034659928 208 SNRQHARLRVCQKI 221
Cdd:cd23275    81 GNRQHSRLRVCQRI 94

Dickkopf N-terminal cysteine-rich region; Dickkopf proteins are a class of Wnt antagonists. They possess two conserved cysteine-rich regions. This family represents the N-terminal one. The C-terminal region has been found to share significant sequence similarity to the colipase fold, pfam01114, pfam02740.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1034659928  40 QCLSDTDCNTRKFCLQPRDEkPFCATCRGLRRRCQRDAMCCPGTLCVNDVCT 91
Cdd:pfam04706   1 ECLSDEDCGKGKYCLSSSGE-SVCLPCRKRRKRCTRDAMCCPGNLCVNGVCV 51

second cysteine-rich (Cys-2) domain of Dickkopf-related protein 4; Dickkopf 4 (Dkk4) is a secreted protein which directly binds to LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and is an inhibitor of Wnt/beta-catenin signaling. Dkk4, which is upregulated by the activated Wnt pathway, contributes to tumor malignancy in variable tumors, promoting tumor cell invasion and progression. Aberrant accumulation of Dkk4 has been shown to promote tumor progression by forming the immune suppressive microenvironment in gastrointestinal stromal tumor, and thus Dkk4 may be used as a tumor biomarker for prognosis prediction and recurrence monitoring. Dkk4 belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dkk4.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034659928 128 KPSIKKSQGRKGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTAQAPEIFQRCDCGPGLLCRSQLT 207
Cdd:cd23275     1 KPGIKKSQSSKGQEGESCLRTSDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTAQGPEIFQRCDCGPGLSCRSQLT 80

                          90
                  ....*....|....
gi 1034659928 208 SNRQHARLRVCQKI 221
Cdd:cd23275    81 GNRQHSRLRVCQRI 94

second cysteine-rich (Cys-2) domain of Dickkopf proteins; The Dickkopf (Dkk) family comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dickkopf proteins 1- 4.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034659928 138 KGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTaqAPEIFQRCDCGPGLLCRSQLTSnrqHARLRV 217
Cdd:cd23012     1 KGREGESCLRSRDCAEGLCCARHLWSKRCKPILLEGDVCTKPRRKKS--RGLIFQRCDCGSGLSCRPQPDS---HKRLHV 75

                  ..
gi 1034659928 218 CQ 219
Cdd:cd23012    76 CQ 77

second cysteine-rich (Cys-2) domain of Dickkopf-related protein 2; Dickkopf 2 (Dkk2) is a secreted protein which directly binds to LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and is an inhibitor of Wnt/beta-catenin signaling. Dkk2 expression is modulated by expression of micro RNA-221 (miRNA-221) in esophageal cancer, and inactivation of Dkk2 may increase Wnt activity with accelerating tumor progression. Dkk2 belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dkk2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034659928 138 KGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDtAQAPEIFQRCDCGPGLLCR-SQLTSNRQHARLR 216
Cdd:cd23273     2 KGHEGDPCLRSSDCAEGFCCARHFWTKICKPVLRQGEVCTKQRRKG-SHGLEIFQRCDCAKGLSCKvWKDATASSKSRLH 80

                  ....
gi 1034659928 217 VCQK 220
Cdd:cd23273    81 VCQK 84

Colipase and the second cysteine-rich (Cys-2) domain of Dickkopf proteins; Colipase (also called CLPS) is a cysteine-rich protein that adopts a similar fold to a cysteine-rich domain (Cys-2) of the Dickkopf (Dkk) family proteins. Colipase functions to prevent the inhibitory effect of bile salts on lipase-catalyzed intraduodenal hydrolysis of dietary long-chain triglycerides. Dickkopf proteins are a discrete class of secreted Wnt inhibitors that are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. They possess an N-terminal signal peptide and contain two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. The Dickkopf Cys-2 domain is similar to proteins in the colipase family and it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034659928 138 KGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRGHKDTaQAPEIFQRCDCGPGLLCRSQ--LTSNRQHARL 215
Cdd:cd23008     1 KGDEGELCLRSSDCKSGNCCARHFWLKICKPVLREGSVCTKFRLKGS-HGLEIFQRCPCERGLSCEGDkdLVGSSTNTRL 79

                  ...
gi 1034659928 216 RVC 218
Cdd:cd23008    80 HIC 82

N-terminus of Dickkopf-related protein 1; includes the first cysteine-rich (Cys-1) domain; Dickkopf-1 (Dkk1) is a secreted protein which directly binds to LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and is an inhibitor of Wnt/beta-catenin signaling. Elevated expression of Dkk-1 may serve as a negative regulator for modulating the wnt/#-catenin signal pathway. Dkk1 is expressed in various human cancers. It has been studied extensively in mouse models of multiple myeloma that results in osteolytic bone lesions. Studies show that Dkk1 levels in bone marrow plasma and serum inhibit the differentiation of osteoblast precursors. Dkk1 belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the N-terminal region of Dkk1, including the Cys-1 domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1034659928  41 CLSDTDCNTRKFCLQPRDE--KPFCATCRGLRRRCQRDAMCCPGTLCVNDVC 90
Cdd:cd23026    70 CAEDEECGTDEYCASPTGVggVQICLACRKRRKRCMRHAMCCPGNYCKNGIC 121

N-terminus of Dickkopf-related protein 3; includes the first cysteine-rich (Cys-1) domain; Dickkopf 3 (Dkk3) is a secreted protein which, in contrast to Dkk1, Dkk2, and Dkk4, does not interact with LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and thus is a divergent family member that is not considered a true Wnt signaling antagonist. The role of Dkk proteins in cancer is considered mainly tumor suppressive since they are usually down-regulated in cancer cells. Dkk3 links heat shock factor 1 (HSF1) and YAP/TAZ signaling to control aggressive behaviors in cancer-associated fibroblasts; it does so via canonical Wnt signaling. It belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the N-terminal region of Dkk3, including the Cys-1 domain and a region to its N-terminus that shows similarity to Dickkopf-like protein 1 (Dkkl1).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1034659928  40 QCLSDTDCNTRKFClQPRDEKPFCATCRGLRRRCQRDAMCCPGTLCVNDVCT 91
Cdd:cd23014   106 ECIIDEDCGPGKYC-QFSSFEYKCQPCKTQDMLCTRDSECCGDQLCVWGHCT 156

second cysteine-rich (Cys-2) domain of Dickkopf-related protein 3; Dickkopf 3 (Dkk3) is a secreted protein which, in contrast to Dkk1, Dkk2, and Dkk4, does not interact with LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and thus is a divergent family member that is not considered a true Wnt signaling antagonist. The role of Dkk proteins in cancer is considered mainly tumor suppressive since they are usually down-regulated in cancer cells. Dkk3 links heat shock factor 1 (HSF1) and YAP/TAZ signaling to control aggressive behaviors in cancer-associated fibroblasts; it does so via canonical Wnt signaling. It belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dkk3.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1034659928 138 KGQEGESCLRTFDCGPGLCCARH--FWTKICKPVLLEGQVCSRRGHKDTAQAPEIFQ------RCDCGPGLLCRSQ 205
Cdd:cd23274     4 KGEAGTICQYQSDCSPGLCCAFHkaLLFPVCTPLPTEGEPCHDPSNHLLDLLSWDLEpegpleHCPCAGGLQCQPH 79